Dual-acting benzoimidazole antihypertensive agents

ABSTRACT

The invention is directed to compounds having the formula: 
                         
wherein: Ar, r, n, X, R 2-3  and R 5-7  are as defined in the specification, and pharmaceutically acceptable salts thereof. These compounds have AT 1  receptor antagonist activity and neprilysin inhibition activity. The invention is also directed to pharmaceutical compositions comprising such compounds; methods of using such compounds; and process and intermediates for preparing such compounds.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.60/933,207, filed on Jun. 5, 2007; the entire disclosure of which isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel compounds having angiotensin IItype 1 (AT₁) receptor antagonist activity and neprilysin-inhibitionactivity. The invention also relates to pharmaceutical compositionscomprising such compounds, processes and intermediates for preparingsuch compounds and methods of using such compounds to treat diseasessuch as hypertension.

2. State of the Art

The aim of antihypertensive therapy is to lower blood pressure andprevent hypertension-related complications such as myocardialinfarction, stroke, and renal disease. For patients with uncomplicatedhypertension (that is, no risk factors, target organ damage, orcardiovascular disease), it is hoped that reducing blood pressure willprevent development of cardiovascular and renal comorbidities,conditions that exist at the same time as the primary condition in thesame patient. For those patients with existing risk factors orcomorbidities, the therapeutic target is the slowing of comorbid diseaseprogression and reduced mortality.

Physicians generally prescribe pharmacological therapies for patientswhose blood pressure cannot be adequately controlled by dietary and/orlifestyle modifications. Commonly used therapeutic classes act topromote diuresis, adrenergic inhibition, or vasodilation. A combinationof drugs is often prescribed, depending upon what comorbidities arepresent.

There are five common drug classes used to treat hypertension:diuretics, which include thiazide and thiazide-like diuretics such ashydrochlorothiazide, loop diuretics such as furosemide, andpotassium-sparing diuretics such as triamterene; β₁ adrenergic receptorblockers such as metoprolol succinate and carvedilol; calcium channelblockers such as amlodipine; angiotensin-converting enzyme (ACE)inhibitors such as captopril, benazepril, enalapril, enalaprilat,lisinopril, quinapril, and ramipril; and AT₁ receptor antagonists, alsoknown as angiotensin II type 1 receptor blockers (ARBs), such ascandesartan cilexetil, eprosartan, irbesartan, losartan, olmesartanmedoxomil, telmisartan, and valsartan. Combinations of these drugs arealso administered, for example, a calcium channel blocker (amlodipine)and an ACE inhibitor (benazepril), or a diuretic (hydrochlorothiazide)and an ACE inhibitor (enalapril). All of these drugs, when usedappropriately, are effective in the treatment of hypertension.Nevertheless, both efficacy and tolerability should be further improvedin new drugs targeting hypertension. Despite the availability of manytreatment options, the recent National Health And Nutrition ExaminationSurvey (NHANES) demonstrated that only about 50% of all treated patientswith hypertension achieve adequate blood pressure control. Furthermore,poor patient compliance due to tolerability issues with availabletreatments further reduces treatment success.

In addition, each of the major classes of antihypertensive agents havesome drawbacks. Diuretics can adversely affect lipid and glucosemetabolism, and are associated with other side effects, includingorthostatic hypotension, hypokalemia, and hyperuricemia. Beta blockerscan cause fatigue, insomnia, and impotence; and some beta blockers canalso cause reduced cardiac output and bradycardia, which may beundesirable in some patient groups. Calcium channel blockers are widelyused but it is debatable as to how effectively these drugs reduce fataland nonfatal cardiac events relative to other drug classes. ACEinhibitors can cause coughing, and rarer side effects include rash,angioedema, hyperkalemia, and functional renal failure. AT₁ receptorantagonists are equally effective as ACE inhibitors but without the highprevalence of cough.

Neprilysin (neutral endopeptidase, EC 3.4.24.11) (NEP), is anendothelial membrane bound Zn²⁺metallopeptidase found in many tissues,including the brain, kidney, lungs, gastrointestinal tract, heart, andperipheral vasculature. NEP is responsible for the degradation andinactivation of a number of vasoactive peptides, such as circulatingbradykinin and angiotensin peptides, as well as the natriureticpeptides, the latter of which have several effects includingvasodilation and diuresis. Thus, NEP plays an important role in bloodpressure homeostasis. NEP inhibitors have been studied as potentialtherapeutics, and include thiorphan, candoxatril, and candoxatrilat. Inaddition, compounds have also been designed that inhibit both NEP andACE, and include omapatrilat, gempatrilat, and sampatrilat. Referred toas vasopeptidase inhibitors, this class of compounds are described inRobl et al. (1999) Exp. Opin. Ther. Patents 9(12): 1665-1677.

There may be an opportunity to increase anti-hypertensive efficacy whencombining AT₁ receptor antagonism and NEP inhibition, as evidenced byAT₁ receptor antagonist/NEP inhibitor combinations described in WO9213564 to Darrow et al (Schering Corporation); US20030144215 to Ksanderet al.; Pu et al., Abstract presented at the Canadian CardiovascularCongress (October 2004); and Gardiner et al. (2006) JPET 319:340-348;and WO 2007/045663 (Novartis AG) to Glasspool et al.

Recently, WO 2007/056546 (Novartis AG) to Feng et al. has describedcomplexes of an AT₁ receptor antagonist and a NEP inhibitor, where anAT₁ receptor antagonist compound is non-covalently bound to a NEPinhibitor compound, or where the antagonist compound is linked vianon-covalent bonding to the inhibitor compound.

In spite of the advances in the art, there remains a need for a highlyefficacious monotherapy with multiple mechanisms of action leading tolevels of blood pressure control that can currently only be achievedwith combination therapy. Thus, although various hypertensive agents areknown, and administered in various combinations, it would be highlydesirable to provide compounds having both AT₁ receptor antagonistactivity and NEP inhibition activity in the same molecule. Compoundspossessing both of these activities are expected to be particularlyuseful as therapeutic agents since they would exhibit antihypertensiveactivity through two independent modes of action while having singlemolecule pharmacokinetics.

In addition, such dual-acting compounds are also expected to haveutility to treat a variety of other diseases that can be treated byantagonizing the AT₁ receptor and/or inhibiting the NEP enzyme.

SUMMARY OF THE INVENTION

The present invention provides novel compounds that have been found topossess AT₁ receptor antagonist activity and neprilysin (NEP) enzymeinhibition activity. Accordingly, compounds of the invention areexpected to be useful and advantageous as therapeutic agents fortreating conditions such as hypertension and heart failure.

One aspect of the invention is directed to a compound of formula I:

wherein:

r is 0, or 2;

Ar is an aryl group selected from:

R¹ is selected from —COOR^(1a), —NHSO₂R^(1b), —SO₂NHR^(1d), —SO₂OH,—C(O)NH—SO₂R^(1c), —P(O)(OH)₂, —CN, —OCH(R^(1e))—COOH, tetrazol-5-yl,

R^(1a) is H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl,—C₃₋₇cycloalkyl, —CH(C₁₋₄alkyl)OC(O)R^(1aa), —C₀₋₆alkylenemorpholine,

R^(1aa) is —O—C₁₋₆alkyl, —O—C₃₋₇cycloalkyl, —NR^(1ab)R^(1ac), or—CH(H₂)CH₂COOCH₃; R^(1ab) and R^(1ac) are independently selected from H,—C₁₋₆alkyl, and benzyl, or are taken together as —(CH₂)₃₋₆—; R^(1b) isR^(1c) or —NHC(O)R^(1c); R^(1c) is —C₁₋₆alkyl, —C₀₋₆alkylene-O—R^(1ca),—C₁₋₅alkylene-NR^(1cb)R^(1cc), —C₀₋₄alkylenearyl or—C₀₋₄alkyleneheteroaryl; R^(1ca) is H, —C₁₋₆alkyl, or—C₁₋₆alkylene-O—C₁₋₆alkyl; R^(1cb) and R^(1cc) are independentlyselected from H and —C₁₋₆alkyl, or are taken together as—(CH₂)₂—O—(CH₂)₂— or —(CH₂)₂—N[C(O)CH₃]—(CH₂)₂—; R^(1d) is H, R^(1c),—C(O)R^(1c), or —C(O)NHR^(1c); R^(1e) is —C₁₋₄alkyl or aryl;

n is 0, 1, 2 or 3;

each R² is independently selected from halo, —NO₂, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₃₋₆cycloalkyl, —CN, —C(O)R^(2a), —C₀₋₅alkylene-OR^(2b),—C₀₋₅alkylene-NR^(2c)R^(2d), —C₀₋₃alkylenearyl, and—C₀₋₃alkyleneheteroaryl; where R^(2a) is selected from H, —C₁₋₆alkyl,—C₃₋₆cycloalkyl, —OR^(2b), and —NR²CR^(2d); R^(2b) is selected from H,—C₁₋₆alkyl, —C₃₋₆cycloalkyl, and —C₀₋₁alkylenearyl; and R^(2c) andR^(2d) are independently selected from H, —C₁₋₄alkyl, and—C₀₋₁alkylenearyl;

R³ is selected from —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₃₋₁₀alkynyl,—C₀₋₃alkylene-C₃₋₇cycloalkyl, —C₂₋₃alkenylene-C₃₋₇cycloalkyl,—C₂₋₃alkynylene-C₃₋₇cycloalkyl,—C₀₋₅alkylene-NR^(3a)C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-S—C₁₋₅alkylene-R^(3b), and —C₀₋₃alkylenearyl; where R^(3a)is selected from H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, and —C₀₋₃alkylenearyl;and R^(3b) is selected from H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl,—C₂₋₄alkenyl, —C₂₋₄alkynyl, and aryl;

X is —C₁₋₁₂alkylene-, where at least one —CH₂— moiety in the alkylene isreplaced with a —NR^(4a)—C(O)— or —C(O)—NR^(4a)— moiety, where R^(4a) isselected from H, —OH, and —C₁₋₄alkyl;

R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁₀alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f),—C₀₋₂alkylene-CHR^(5g)—COOH, —C₀₋₃alkylene-C(O)NR^(5h)CHR^(5i)—COOH, and—C₀₋₃alkylene-S—SR^(5j); where R^(5a) is H or —C(O)—R^(5aa); R^(5aa) is—C₁₋₆alkyl, —C₀₋₆alkylene-C₃₋₇cycloalkyl, -aminoC₄₋₇cycloalkyl,—C₀₋₆alkylenearyl, —C₀₋₆alkyleneheteroaryl, —C₀₋₆alkylenemorpholine,—C₀₋₆alkylenepiperazine-CH₃, —C₀₋₆alkylenepiperidine,—C₀₋₆alkylenepiperidine-CH₃, —CH[N(R^(5ab))₂]-aa where aa is an aminoacid side chain, —C₀₋₆alkylene-CH[N(R^(5ab))₂]—R^(5ac), -2-pyrrolidine,-2-tetrahydrofuran, —C₀₋₆alkylenearyl-OR^(5ab), —O—C₀₋₆alkylenearyl,—C₁₋₂alkylene-OC(O)—C₁₋₆alkyl, —C₁₋₂alkylene-OC(O)—C₀₋₆alkylenearyl,—O—C₁₋₂alkylene-OC(O)O—C₁₋₆alkyl, —C₁₋₄alkylene-COOH, or -arylene-COOH;R^(5ab) is independently H or —C₁₋₆alkyl; R^(5ac), is H, —C₁₋₆alkyl,—CH₂—C₃₋₇cycloalkyl or —COOH; R^(5b) is selected from H, —OH,—OC(O)R^(5ba), —CH₂COOH, —O-benzyl, -pyridyl, or —OC(S)NR^(5bb)R^(5bc);R^(5ba) is H, —C₁₋₆alkyl, aryl, —OCH₂-aryl, —CH₂O-aryl, or—NR^(5bb)R^(5b); R^(5bb) and R^(5bc) are independently selected from Hand —C₁₋₄alkyl; R^(5c) is H, —C₁₋₆alkyl, or —C(O)R^(5ca); R^(5ca) is—C₁₋₆alkyl, —C₃₋₇cycloalkyl, aryl, or heteroaryl; R^(5d) is H,—C₁₋₄alkyl, —C₀₋₃alkylenearyl, —NR^(5da)R^(5db), —CH₂SH, or—O—C₁₋₆alkyl; R^(5da) and R^(5db) are independently selected from H and—C₁₋₄alkyl; R^(5e) is H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl,—C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl, —CH(CH₃)OC(O)R^(5ca),

R^(5ea) is —O—C₁₋₆alkyl, —O—C₃₋₇cycloalkyl, —NR^(5eb)R^(5ec), or—CH(NH₂)CH₂COOCH₃; R^(5eb) and R^(5ec) are independently selected fromH, —C₁₋₄alkyl, and —C₁₋₃alkylenearyl, or are taken together as—(CH₂)₃₋₆—; R^(5f) is selected from H, —C₁₋₄alkyl, —C₀₋₃alkylenearyl,—C₁₋₃alkylene-NR^(5fa)R^(5fb), and—C₁₋₃alkylene(aryl)-C₀₋₃alkylene-NR^(5fa)R^(5fb); R^(5fa) and R^(5b) areindependently selected from H and —C₁₋₄alkyl; R^(5g) is H, —C₁₋₆alkyl,—C₁₋₃alkylenearyl, or —CH₂—O—(CH₂)₂—OCH₃; R^(5h) is H or —C₁₋₄alkyl;R^(5i) is H, —C₁₋₄alkyl, or —C₀₋₃alkylenearyl; and R^(5j) is —C₁₋₆alkyl,aryl, or —CH₂CH(NH₂)COOH;

R⁶ is selected from —C₁₋₆alkyl, —CH₂O(CH₂)₂OCH₃,—C₁₋₆alkylene-O—C₁₋₆alkyl, —C₀₋₃alkylenearyl, —C₀₋₃alkyleneheteroaryl,and —C₀₋₃alkylene-C₃₋₇cycloalkyl; and

R⁷ is H or is taken together with R⁶ to form —C₃₋₈cycloalkyl;

wherein: each —CH₂— group in —(CH₂)_(r)— is optionally substituted with1 or 2 substituents independently selected from —C₁₋₄alkyl and fluoro;each carbon atom in the alkylene moiety in X is optionally substitutedwith one or more R^(4b) groups and one —CH₂-moiety in X may be replacedwith a group selected from —C₃₋₈cycloalkylene-, —CR^(4d)═CH—, and—CH═CR^(4d)—; wherein R^(4b) is selected from —C₀₋₅alkylene-COOR^(4c),—C₁₋₆alkyl, —C₀₋₁alkylene-CONH₂, —C₁₋₂alkylene-OH,—C₀₋₃alkylene-C₃₋₇cycloalkyl, 1H-indol-3-yl, benzyl, and hydroxybenzyl;R^(4c) is H or —C₁₋₄alkyl; and R^(4d) is selected from —CH₂-thiopheneand phenyl; each alkyl and each aryl in R¹⁻³, R^(4a-4d), and R⁵⁻⁶ isoptionally substituted with 1 to 7 fluoro atoms; each ring in Ar andeach aryl and heteroaryl in R¹⁻³ and R⁵⁻⁶ is optionally substituted with1 to 3 substituents independently selected from —OH, —C₁₋₆alkyl,—C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,—S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, -phenyl, —NO₂, —NH₂, —NH—C₁₋₆alkyland —N(C₁₋₆alkyl)₂, wherein each alkyl, alkenyl and alkynyl isoptionally substituted with 1 to 5 fluoro atoms; and pharmaceuticallyacceptable salts thereof.

Another aspect of the invention relates to pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and a compound of theinvention. Such compositions may optionally contain other therapeuticagents such as diuretics, β₁ adrenergic receptor blockers, calciumchannel blockers, angiotensin-converting enzyme inhibitors, AT₁ receptorantagonists, neprilysin inhibitors, non-steroidal anti-inflammatoryagents, prostaglandins, anti-lipid agents, anti-diabetic agents,anti-thrombotic agents, renin inhibitors, endothelin receptorantagonists, endothelin converting enzyme inhibitors, aldosteroneantagonists, angiotensin-converting enzyme/neprilysin inhibitors,vasopressin receptor antagonists, and combinations thereof. Accordingly,in yet another aspect of the invention, a pharmaceutical compositioncomprises a compound of the invention, a second therapeutic agent, and apharmaceutically acceptable carrier. Another aspect of the inventionpertains to a combination of active agents, comprising a compound of theinvention and a second therapeutic agent. The compound of the inventioncan be formulated together or separately from the additional agent(s).When formulated separately, a pharmaceutically acceptable carrier may beincluded with the additional agent(s). Thus, yet another aspect of theinvention relates to a combination of pharmaceutical compositions, thecombination comprising: a first pharmaceutical composition comprising acompound of the invention and a first pharmaceutically acceptablecarrier; and a second pharmaceutical composition comprising a secondtherapeutic agent and a second pharmaceutically acceptable carrier. Theinvention also relates to a kit containing such pharmaceuticalcompositions, for example where the first and second pharmaceuticalcompositions are separate pharmaceutical compositions.

Compounds of the invention possess both AT₁ receptor antagonist activityand NEP enzyme inhibition activity, and are therefore expected to beuseful as therapeutic agents for treating patients suffering from adisease or disorder that is treated by antagonizing the AT₁ receptorand/or inhibiting the NEP enzyme. Thus, one aspect of the invention isdirected to a method of treating patients suffering from a disease ordisorder that is treated by antagonizing the AT₁ receptor and/orinhibiting the NEP enzyme, comprising administering to a patient atherapeutically effective amount of a compound of the invention. Anotheraspect of the invention is directed to a method of treating hypertensionor heart failure, comprising administering to a patient atherapeutically effective amount of a compound of the invention. Stillanother aspect of the invention pertains to a method for antagonizing anAT₁ receptor in a mammal comprising administering to the mammal, an AT₁receptor-antagonizing amount of a compound of the invention. Yet anotheraspect of the invention pertains to a method for inhibiting a NEP enzymein a mammal comprising administering to the mammal, a NEPenzyme-inhibiting amount of a compound of the invention.

Compounds of formula I and pharmaceutically acceptable salts thereof,that are of particular interest include those that exhibit an inhibitoryconstant (pK_(i)) for binding to an AT₁ receptor greater than or equalto about 5.0; in particular those having a pK_(i) greater than or equalto about 6.0; in one embodiment those having a pK_(i) greater than orequal to about 7.0; more particularly those having a pK_(i) greater thanor equal to about 8.0; and in yet another embodiment, those having apK_(i) within the range of about 8.0-10.0. Compounds of particularinterest also include those having a NEP enzyme inhibitory concentration(pIC₅₀) greater than or equal to about 5.0; in one embodiment thosehaving a pIC₅₀ greater than or equal to about 6.0; in particular thosehaving a pIC₅₀ greater than or equal to about 7.0; and most particularlythose having a pIC₅₀ within the range of about 7.0-10.0. Compounds offurther interest include those having a pK_(i) for binding to an AT₁receptor greater than or equal to about 7.5 and having a NEP enzymepIC₅₀ greater than or equal to about 7.0.

Since compounds of the invention possess AT₁ receptor antagonistactivity and NEP inhibition activity, such compounds are also useful asresearch tools. Accordingly, one aspect of the invention pertains to amethod of using a compound of the invention as a research tool, themethod comprising conducting a biological assay using a compound of theinvention. Compounds of the invention can also be used to evaluate newchemical compounds. Thus another aspect of the invention relates to amethod of evaluating a test compound in a biological assay, comprising:(a) conducting a biological assay with a test compound to provide afirst assay value; (b) conducting the biological assay with a compoundof the invention to provide a second assay value; wherein step (a) isconducted either before, after or concurrently with step (b); and (c)comparing the first assay value from step (a) with the second assayvalue from step (b). Exemplary biological assays include an AT₁ receptorbinding assay and a NEP enzyme inhibition assay. Still another aspect ofthe invention is directed to a method of studying a biological system orsample comprising an AT₁ receptor, a NEP enzyme, or both, the methodcomprising: (a) contacting the biological system or sample with acompound of the invention; and (b) determining the effects caused by thecompound on the biological system or sample.

The invention is also directed to processes and intermediates useful forpreparing compounds of the invention. Accordingly, another aspect of theinvention relates to a process of preparing compounds of the inventioncomprising the step of coupling a compound of formula 1 with a compoundof formula 2:

where: A is —NH₂ and B is —COOH or A is —COOH and B is —NH₂; the sum ofa and b is in the range of 0 to 1; Ar* represents Ar—R¹*, where R¹* isR¹ or a protected form of R¹; and R⁵* represents R⁵ or a protected formof R⁵; the carbon atoms in the —(CH₂)_(a) and —(CH₂)_(b) groups may besubstituted with one or more R^(4b) groups; and one —CH₂— group in the—(CH₂)_(a) or the —(CH₂)_(b) group may be replaced with—C₃₋₈cycloalkylene-, —CR^(4d)═CH—, or —CH═CR^(4d)—; and optionallydeprotecting the product when R¹* is a protected form of R¹ and/or R⁵*is a protected form of R⁵. Another aspect of the invention relates to aprocess of preparing a pharmaceutically acceptable salt of a compound offormula I, comprising contacting a compound of formula I in free acid orbase form with a pharmaceutically acceptable base or acid. In otheraspects, the invention is directed to products prepared by any of theprocesses described herein, as well as novel intermediates used in suchprocess. In one aspect of the invention novel intermediates have formulaII, III or IV, as defined herein.

Yet another aspect of the invention is directed to the use of a compoundof formula I or a pharmaceutically acceptable salt thereof, for themanufacture of a medicament, especially for the manufacture of amedicament useful for treating hypertension or heart failure. Anotheraspect of the invention is directed to use of a compound of theinvention for antagonizing an AT₁ receptor or for inhibiting a NEPenzyme in a mammal. Still another aspect of the invention pertains tothe use of a compound of the invention as a research tool. Other aspectsand embodiments of the invention are disclosed herein.

DETAILED DESCRIPTION OF THE INVENTION

The invention is directed to compounds of formula I:

and pharmaceutically acceptable salts thereof.

As used herein, the term “compound of the invention” is intended toinclude compounds of formula I as well as the species embodied informulas Ia, Ia-1, Ia-2, Ia-3, Ib, Ib-1, Ib-2, Ib-3, Ic and Id,described below. In addition, the compounds of the invention may alsocontain several basic or acidic groups (e.g., amino or carboxyl groups)and therefore, such compounds can exist as a free base, free acid, or invarious salt forms. All such salt forms are included within the scope ofthe invention. Furthermore, solvates of compounds of formula I or saltsthereof are included within the scope of the invention. Finally, thecompounds of the invention may also exist as prodrugs. Accordingly,those skilled in the art will recognize that reference to a compoundherein, for example, reference to a “compound of the invention” includesreference to a compound of formula I as well as to pharmaceuticallyacceptable salts, solvates and prodrugs of that compound unlessotherwise indicated. Further, the term “or a pharmaceutically acceptablesalt, solvate and/or prodrug thereof” is intended to include allpermutations of salts and solvates, such as a solvate of apharmaceutically acceptable salt.

The compounds of formula I may contain one or more chiral centers and somay exist in a number of stereoisomeric forms. When such chiral centersare present, the invention is directed to racemic mixtures, purestereoisomers (i.e., enantiomers or diastereomers),stereoisomer-enriched mixtures, and the like unless otherwise indicated.When a chemical structure is depicted without any stereochemistry, it isunderstood that all possible stereoisomers are encompassed by suchstructure. Thus, for example, the term “compound of formula I” isintended to include all possible stereoisomers of the compound.Similarly, when a particular stereoisomer is shown or named herein, itwill be understood by those skilled in the art that minor amounts ofother stereoisomers may be present in the compositions of the inventionunless otherwise indicated, provided that the utility of the compositionas a whole is not eliminated by the presence of such other isomers.Individual enantiomers may be obtained by numerous methods that are wellknown in the art, including chiral chromatography using a suitablechiral stationary phase or support, or by chemically converting theminto diastereomers, separating the diastereomers by conventional meanssuch as chromatography or recrystallization, then regenerating theoriginal enantiomers. Additionally, where applicable, all cis-trans orE/Z isomers (geometric isomers), tautomeric forms and topoisomeric formsof the compounds of the invention are included within the scope of theinvention unless otherwise specified.

Compounds of formula I may contain one or more chiral centers. Onepossible chiral center could be present in the X portion of thecompound. For example, a chiral center exists at a carbon atom in thealkylene moiety in X that is substituted with an R^(4b) group such as—C₁₋₆alkyl, for example —CH₃. This chiral center is present at thecarbon atom indicated by the symbol * in the following partial formula:

Another possible chiral center could be present in the —CR⁵R⁶R⁷ portionof the compound, when R⁶ is a group such as —C₁₋₆alkyl, for example—CH₂CH(CH₃)₂, and R⁷ is H. This chiral center is present at the carbonatom indicated by the symbol ** in the following formula:

In one embodiment of the invention, the carbon atom identified by thesymbol * and/or** has the (R) configuration. In this embodiment,compounds of formula I have the (R) configuration at the carbon atomidentified by the symbol * and/or ** or are enriched in a stereoisomericform having the (R) configuration at this carbon atom (or atoms). Inanother embodiment, the carbon atom identified by the symbol * and/or **has the (S) configuration. In this embodiment, compounds of formula Ihave the (S) configuration at the carbon atom identified by the symbol *and/or ** or are enriched in a stereoisomeric form having the (S)configuration at this carbon atom. It is understood that a compound mayhave a chiral center at both the * and the ** carbon atoms. In suchcases, four possible diastereomers can exist. In some cases, in order tooptimize the therapeutic activity of the compounds of the invention, forexample, as hypertensive agents, it may be desirable that the carbonatom identified by the symbol * and/or ** have a particular (R) or (S)configuration.

The compounds of the invention, as well as those compounds used in theirsynthesis, may also include isotopically-labeled compounds, that is,where one or more atoms have been enriched with atoms having an atomicmass different from the atomic mass predominately found in nature.Examples of isotopes that may be incorporated into the compounds offormula I, for example, include, but are not limited to, ²H, ³H, ¹³C,¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³⁵S, ³⁶Cl, and ¹⁸F.

The compounds of formula I have been found to possess AT₁ receptorantagonizing activity and NEP enzyme inhibition activity. Among otherproperties, such compounds are expected to be useful as therapeuticagents for treating diseases such as hypertension. By combining dualactivity into a single compound, double therapy can be achieved, thatis, AT₁ receptor antagonist activity and NEP enzyme inhibition activitycan be obtained using a single active component. Since pharmaceuticalcompositions containing one active component are typically easier toformulate than compositions containing two active components, suchsingle-component compositions provide a significant advantage overcompositions containing two active components. In addition, certaincompounds of the invention have also been found to be selective forinhibition of the AT₁ receptor over the angiotensin II type 2 (AT₂)receptor, a property that may have therapeutic advantages.

The nomenclature used herein to name the compounds of the invention isillustrated in the Examples herein. This nomenclature has been derivedusing the commercially available AutoNom software (MDL, San Leandro,Calif.).

Representative Embodiments

The following substituents and values are intended to providerepresentative examples of various aspects and embodiments of theinvention. These representative values are intended to further defineand illustrate such aspects and embodiments and are not intended toexclude other embodiments or to limit the scope of the invention. Inthis regard, the representation that a particular value or substituentis preferred is not intended in any way to exclude other values orsubstituents from the invention unless specifically indicated.

The invention is directed to compounds of formula I:

The values for r are 0, 1 or 2. In one embodiment, r is 1. Each —CH₂—group in the —(CH₂)_(r)— group may be substituted with 1 or 2substituents independently selected from —C₁₋₄alkyl (for example, —CH₃)and fluoro. In one particular embodiment, the —(CH₂)_(r)— group isunsubstituted; in another embodiment, one or two —CH₂— groups in—(CH₂)_(r)— are substituted with a —C₁₋₄alkyl group.

Ar represents an aryl group selected from:

Each ring in the Ar moiety may be substituted with 1 to 3 substituentsindependently selected from —OH, —C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl,—CN, halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl,—S(O)₂—C₁₋₄alkyl, -phenyl, —NO₂, —NH₂, —NH—C₁₋₆alkyl and —N(C₁₋₆alkyl)₂.Furthermore, each of the aforementioned alkyl, alkenyl and alkynylgroups are optionally substituted with 1 to 5 fluoro atoms.

In one particular embodiment, each ring in the Ar moiety may besubstituted with 1 to 2 substituents independently selected from —OH,—C₁₋₄alkyl (for example, —CH₃), halo (for example bromo, fluoro, chloro,and di-fluoro), —O—C₁₋₄alkyl (for example, —OCH₃), and -phenyl.Exemplary substituted Ar moieties include:

Of particular interest is where Ar is substituted with 1 or 2 haloatoms, particularly fluoro or chloro atoms.

It is understood that the Ar structure:

In one particular embodiment, Ar is an aryl group selected from:

where Ar is optionally substituted with one fluoro, chloro or bromoatom.

R¹ is selected from —COOR^(1a), —NHSO₂R^(1b), —SO₂NHRM d, —SO₂OH,—C(O)NH—SO₂R^(1c), —P(O)(OH)₂, —CN, —OCH(R^(1e))—COOH, tetrazol-5-yl,

The R^(1a) moiety is H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl,—C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl, —CH(C₁₋₄alkyl)OC(O)R^(1aa),—C₀₋₆alkylenemorpholine,

R^(1aa) is —O—C₁₋₆alkyl, —O—C₃₋₇cycloalkyl, —NR^(1ab)R^(1ac), or—CH(NH₂)CH₂COOCH₃. R^(1ab) and R^(1ac) are independently selected fromH, —C₁₋₆alkyl, and benzyl, or are taken together to form —(CH₂)₃₋₆—.

The R^(1b) moiety is R^(1c) or —NHC(O)R^(1c). The R^(1c) group is—C₁₋₆alkyl, —C₀₋₆alkylene-O—R^(1ca), —NR^(1cb)R^(1cc), or—C₀₋₄alkylenearyl. The R^(1ca) moiety is H, —C₁₋₆alkyl, or—C₁₋₆alkylene-O—C₁₋₆alkyl. The R^(1cb) and R^(1cc) groups areindependently selected from H and —C₁₋₆alkyl, or are taken together as—(CH₂)₂—O—(CH₂)₂— or —(CH₂)₂—N[C(O)CH₃]-(CH₂)₂—. The R^(1d) moiety is H,R^(1c), —C(O)R^(1c), or —C(O)NHR^(1c). The R^(1c) group is —C₁₋₄alkyl oraryl.

In one embodiment, R¹ is —COOR^(1a) and R^(1a) is H. In anotherembodiment, R¹ is COOR^(1a) and R^(1a) is —C₁₋₆alkyl, examples of whichinclude —CH₃, —CH₂CH₃, —(CH₂)₂CH₃, —(CH₂)₂—CF₃, —CH(CH₃)₂, —CH(CH₂F)₂,—CH(CH₃)CF₃, —CH₂CH(CH₃)₂—C(CH₃)₃, —(CH₂)₃CH₃, and —(CH₂)₂—CF₂CF₃. Thus,examples of R¹ include —C(O)OCH₃, —C(O)OCH₂CH₃, —C(O)O—(CH₂)₂CH₃,—C(O)O—CH₂CH(CH₃)₂, —C(O)OC(CH₃)₃, —C(O)O—(CH₂)₃CH₃, and so forth.

In one embodiment, R¹ is —COOR^(1a) and R^(1a) is —C₁₋₃alkylenearyl, forexample, a benzyl group, which may be substituted, examples of whichinclude chlorobenzyl such as 3-chlorobenzyl and 4-chlorobenzyl,fluorobenzyl such as 3-fluorobenzyl, difluorobenzyl such as2,6-difluorobenzyl, methylbenzyl such as 4-methylbenzyl, methoxybenzylsuch as 3-methoxybenzyl, -benzyl-CF₃, and -benzyl-O—CF₃. Thus, examplesof R¹ include —C(O)OCH₂-benzyl,

In one embodiment, R¹ is —COOR^(1a) and R^(1a) is—C₁₋₃alkyleneheteroaryl, examples of which include —CH₂-pyridinyl. Inone embodiment, R¹ is —COOR^(1a) and R^(1a) is —C₃₋₇cycloalkyl, examplesof which include cyclopentyl.

In yet another embodiment R¹ is —COOR^(1a) and R^(1a) is—CH(C₁₋₄alkyl)OC(O)R^(1aa), where R^(1aa) is —O—C₁₋₆alkyl,—O—C₃₋₇cycloalkyl, —NR^(1ab)R^(1ac), or —CH(NH₂)CH₂COOCH₃. R^(1ab) andR^(1ac) are independently selected from H, —C₁₋₆alkyl, and benzyl, orare taken together to form —(CH₂)₃₋₆—. Examples of —O—C₁₋₆alkyl groupsinclude —O—CH₂CH₃ and —O—CH(CH₃)₂. Exemplary —O—C₃₋₇cycloalkyl groupsinclude —O-cyclohexyl. Thus, examples of R¹ include—C(O)OCH(CH₃)OC(O)—O—CH₂CH₃, —C(O)OCH(CH₃)OC(O)—O—CH(CH₃)₂, and—C(O)OCH(CH₃)OC(O)—O-cyclohexyl.

In one embodiment, R¹ is —COOR^(1a) and R^(1a) is—C₀₋₆alkylenemorpholine, examples of which include —(CH₂)₂-morpholineand —(CH₂)₃-morpholine, thus one example of R¹ is—C(O)O(CH₂)₃-morpholin-4-yl. In another embodiment, R^(1a) is

For example, R¹ may be:

In one embodiment, R¹ is —NHSO₂R^(1b) and R^(1b) is R^(1c). The R^(1c)group can be —C₁₋₆alkyl, —C₁₋₆alkylene-O—R^(1ca), —C₁₋₅alkylene-NRcbR^(1cc), —C₀₋₄alkylenearyl or —C₀₋₄alkyleneheteroaryl. The R^(1ca)moiety is H, —C₁₋₆alkyl, or —C₁₋₆alkylene-O—C₁₋₆alkyl. The R^(1cb) andR^(1cc) groups are independently selected from H and —C₁₋₆alkyl, or aretaken together as —(CH₂)₂—O—(CH₂)₂— or —(CH₂)₂—N[C(O)CH₃]-(CH₂)₂—. Inone embodiment, R^(1c) is —C₁₋₆alkyl, such that exemplary R¹ groupsinclude —NHSO₂—CH₃ and the fluoro-substituted group, —NHSO₂—CF₃. Inanother embodiment, R^(1c) is —C₀₋₄alkylenearyl, such that exemplary R¹groups include —NHSO₂-phenyl. In another embodiment, R^(1c) is—C₀₋₄alkyleneheteroaryl, such that exemplary R¹ groups include—NHSO₂-4,5-dimethylisoxazol-3-yl.

In another embodiment, R¹ is —NHSO₂R^(1b) and R^(1b) is —NHC(O)R^(1c),where R^(1c) is defined above. In a particular embodiment, R¹ is—NHSO₂R^(1b), R^(1b) is —NHC(O)R^(1c), and R^(1c) is —C₁₋₆alkyl or—C₀₋₄alkylenearyl.

In one embodiment, R¹ is —SO₂NR^(1d) and R^(1d) is H. In anotherembodiment, R¹ is —SO₂NHR^(1d) and R^(1d) is R^(1c), where R^(1c) isdefined above. In a particular embodiment, R^(1c) is —C₁₋₆alkyl or—C₀₋₄alkylenearyl. When R^(1c) is —C₁₋₆alkyl, exemplary R¹ groupsinclude the fluoro-substituted groups —SO₂NH—CF₃, —SO₂NH—CHF₂,—SO₂NH—CF₂CH₂F and —SO₂NH—CF₂CF₂CF₃.

In another embodiment, R¹ is —SO₂NHR^(1d) and R^(1d) is —C(O)R^(1c),where R^(1c) is defined above. In one embodiment of particular interest,R^(1c) is —C₁₋₆alkyl or —C₀₋₄alkylenearyl. When R^(1c) is —C₁₋₆alkyl,exemplary R¹ groups include —SO₂NHC(O)CH₃ and —SO₂NHC(O)—(CH₂)₂CH₃. WhenR^(1c) is —C₀₋₆alkylene-O—R^(1ca) and R^(1ca) is H, exemplary R¹ groupsinclude —SO₂NHC(O)CH₂OH, —SO₂NHC(O)CH(CH₃)OH, and —SO₂NHC(O)C(CH₃)₂OH.When R^(1c) is —C₀₋₆alkylene-O—R^(1ca) and R^(1ca) is —C₁₋₆alkyl,exemplary R¹ groups include —SO₂NHC(O)CH₂—O—CH₃, —SO₂NHC(O)—O—CH₃, and—SO₂NHC(O)—O—CH₂CH₃. When R^(1c) is —C₀₋₆alkylene-O—R^(1ca) and R^(1ca)is —C₁₋₆alkylene-O—C₁₋₆alkyl, exemplary R¹ groups include—SO₂NHC(O)CH₂—O—(CH₂)₂—O—CH₃. When R^(1c) is—C₁₋₅alkylene-NR^(1cb)R^(1cc), exemplary R¹ groups include—SO₂NHC(O)CH₂N(CH₃)₂, —SO₂NHC(O)CH₂NH₂, and —SO₂NHC(O)—CH(CH₃)(NH₂).Another example when R^(1c) is —C₁₋₅alkylene-NR^(1cb)R^(1cc) is wherethe R^(1cb) and R^(1cc) are taken together as —(CH₂)₂—O—(CH₂)₂— or—(CH₂)₂—N[C(O)CH₃]-(CH₂)₂—. Such exemplary R¹ groups include:

When R^(1c) is —C₀₋₄alkylenearyl, exemplary R¹ groups include—SO₂NHC(O)-phenyl.

In another embodiment, R¹ is —SO₂NHR^(1d) and R^(1d) is —C(O)NHR^(1c),where R^(1c) is defined above. In a particular embodiment, R^(1c) is—C₁₋₆alkyl or —C₀₋₄alkylenearyl. When R^(1c) is —C₁₋₆alkyl, exemplary R¹groups include —SO₂NHC(O)NH—CH₂CH₃ and —SO₂NHC(O)NH—(CH₂)₂CH₃. WhenR^(1c) is —C₀₋₄alkylenearyl, exemplary R¹ groups include—SO₂NHC(O)NH-phenyl.

In another embodiment, R¹ is —SO₂OH, and in still another embodiment, R¹is —P(O)(OH)₂. In yet another embodiment, R¹ is —CN.

In another embodiment, R¹ is —C(O)NH—SO₂R^(1c), where R^(1c) is definedabove. In a particular embodiment, R^(1c) is —C₁₋₆alkyl or—C₀₋₄alkylenearyl. When R^(1c) is —C₁₋₆alkyl, exemplary R¹ groupsinclude —C(O)NH—SO₂—CH₃, —C(O)NH—SO₂—CH₂CH₃ and the fluoro-substituted—C(O)NH—SO₂—CF₃ group.

In another embodiment, R¹ is —O—CH(R^(1e))—COOH, where R^(1e) is—C₁₋₄alkyl or aryl. Examples of such R¹ groups include, —O—CH(CH₃)—COOHand —O—CH(phenyl)-COOH.

In an embodiment of particular interest, R¹ is tetrazol-5-yl. In anotherembodiment, R¹ is:

Each alkyl and each aryl in R¹ is optionally substituted with 1 to 7fluoro atoms. In addition, the term “alkyl” is intended to includedivalent alkylene groups such as those present in —C₁₋₃alkylenearyl and—C₁₋₃alkyleneheteroaryl, for example.

Further, each aryl and heteroaryl group that might be present in R¹ maybe substituted with 1 to 3 —OH, —C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl,—CN, halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl,—S(O)₂—C₁₋₄alkyl, -phenyl, —NO₂, —NH₂, —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)₂groups. Further, each of the aforementioned alkyl, alkenyl and alkynylgroups may be substituted with 1 to 5 fluoro atoms. It is understoodthat when referring to “each alkyl,” “each aryl” and “each heteroaryl”in R¹, the term also includes any alkyl, aryl, and heteroaryl groupsthat might be present in the R^(1a) through R^(1e) moieties.

The values for n are 0, 1, 2 or 3. In one embodiment, n is 0. In anotherembodiment, n is 1, and in one particular embodiment, R² is at the 4position of the benzoimidazole ring, as depicted below:

Each R² is independently selected from halo, —NO₂, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₃₋₆cycloalkyl, —CN, —C(O)R^(2a), —C₀₋₅alkylene-OR^(2b),—C₀₋₅alkylene-NR^(2c)R^(2d), —C₀₋₃alkylenearyl, and—C₀₋₃alkyleneheteroaryl. The R^(2a) moiety is H, —C₁₋₆alkyl,—C₃₋₆cycloalkyl, —OR^(2b), or —NR^(2c)R^(2d). R^(2b) is selected from H,—C₁₋₆alkyl, —C₃₋₆cycloalkyl, and —C₀₋₁alkylenearyl; and R^(2c) andR^(2d) are independently selected from H, —C₁₋₄alkyl, and—C₀₋₁alkylenearyl.

In one particular embodiment, R² is halo, for example, chloro. In yetanother embodiment, R² is —C₁₋₆alkyl such as —CH₃, andfluoro-substituted alkyl groups such as —CH₂F and —CF₃. In anotherembodiment R² is —C₀₋₅alkylene-OR^(2b) and R^(2b) is H; one such R²group is —CH₂OH.

Each alkyl and each aryl in R² is optionally substituted with 1 to 7fluoro atoms. It is understood that when referring to the “alkyl” in R²,the term includes any alkyl groups that might be present in the R^(2a),R^(2b), R^(2c) and R^(2d) moieties. In addition, each aryl andheteroaryl in R², for example in —C₀₋₃alkylenearyl and—C₀₋₃alkyleneheteroaryl, may be substituted with 1 to 3 —OH, —C₁₋₆alkyl,—C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,—S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, -phenyl, —NO₂, —NH₂, —NH—C₁₋₆alkyl,or —N(C₁₋₆alkyl)₂ groups. Further, each of the aforementioned alkyl,alkenyl and alkynyl groups may be substituted with 1 to 5 fluoro atoms.It is understood that when referring to the “aryl” or the “heteroaryl”in R², the term includes any aryl groups that might be present in theR^(2a), R^(2b), R^(2c) and R^(2d) moieties.

R³ is selected from —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₃₋₁₀alkynyl,—C₀₋₃alkylene-C₃₋₇cycloalkyl, —C₂₋₃alkenylene-C₃₋₇cycloalkyl,—C₂₋₃alkynylene-C₃₋₇cycloalkyl,—C₀₋₅alkylene-NR^(3a)—C₀₋₅alkylene-S—C₁₋₅alkylene-R^(3b), and—C₀₋₃alkylenearyl. R^(3a) can be H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, or—C₀₋₃alkylenearyl (for example, —C₀₋₁alkylenearyl such as phenyl andbenzyl). R^(3b) can be H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₂₋₄alkenyl,—C₂₋₄alkynyl, or aryl (such as phenyl).

In addition, each alkyl and each aryl in R³ is optionally substitutedwith 1 to 7 fluoro atoms, where the term “alkyl” is intended to includedivalent alkylene groups such as those present in—C₀₋₃alkylene-C₃₋₇cycloalkyl and —C₀₋₃alkylenearyl, for example. Eacharyl in R³, for example in —C₀₋₃alkylenearyl or phenyl, may besubstituted with 1 to 3 —OH, —C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl,—CN, halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl —S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl,-phenyl, —NO₂, —NH₂, —NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)₂ groups. Further,each of the aforementioned alkyl, alkenyl and alkynyl groups may besubstituted with 1 to 5 fluoro atoms. It is understood that whenreferring to “each alkyl” or “each aryl” in R³, the term includes anyalkyl and aryl groups that might be present in the R^(3a) and R^(3b)moieties.

In one embodiment, R³ is —C₁₋₁₀alkyl, examples of which include,—CH₂CH₃, —(CH₂)₂CH₃, and —(CH₂)₃CH₃. In another embodiment, R³ is—C₂₋₇alkyl; and in yet another embodiment, R³ is —C₂₋₅alkyl, forexample, —(CH₂)₂CH₃.

In another embodiment, R³ is —C₂₋₁₀alkenyl such as —CH₂CH═CHCH₃. In yetanother embodiment, R³ is —C₃₋₁₀alkynyl such as —CH₂C≡CCH₃.

In another embodiment, R³ is —C₀₋₃alkylene-C₃₋₇cycloalkyl such as-cyclopropyl, —CH₂-cyclopropyl, cyclopentyl, —CH₂-cyclopentyl,—(CH₂)₂-cyclopentyl, and —CH₂-cyclohexyl. In a particular embodiment, R³is —C₀₋₁alkylene-C₃₋₅cycloalkyl. In one embodiment, R³ is—C₂₋₃alkenylene-C₃₋₇cycloalkyl such as —CH₂CH═CH-cyclopentyl; and inanother embodiment, R³ is —C₂₋₃alkynylene-C₃₋₇cycloalkyl such as—CH₂C≡C-cyclopentyl.

In yet another embodiment, R³ is—C₀₋₅alkylene-NR^(3a)—C₀₋₅alkylene-R^(3b). In one particular embodiment,R^(3a) is H and R^(3b) is —C₁₋₆alkyl. Examples of such R³ groups include—NHCH₂CH₃, —NHCH(CH₃)₂, —NH(CH₂)₂CH₃, —NH(CH₂)₃CH₃, —NHCH(CH₃)CH₂CH₃,—NH(CH₂)₄CH₃, and —NH(CH₂)₅CH₃.

In one embodiment, R³ is —C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b). In oneparticular embodiment, R^(3b) is selected from H, —C₁₋₆alkyl and aryl.Examples of such R³ groups include —OCH₃, —OCH₂CH₃, —OCH(CH₃)₂,—O(CH₂)₂CH₃, —O(CH₂)₃CH₃, —OCH₂CH(CH₃)₂, —O-phenyl, and —O-benzyl. Inanother embodiment, R³ is —C₀₋₅alkylene-O—C₀₋₅alkylene-R where R^(3b) is—C₁₋₆alkyl, and in another embodiment, R³ is —O—C₁₋₅alkyl.

In another embodiment, R³ is —C₀₋₅alkylene-S—C₁₋₅alkylene-R^(3b), and inone particular embodiment R^(3b) is H, such as when R³ is —CH₂—S—CH₂CH₃.In another embodiment, R³ is —C₀₋₃alkylenearyl, such as phenyl, benzyl,and —(CH₂)₂-phenyl.

X is —C₁₋₁₂alkylene-, where at least one —CH₂— moiety in the alkylene isreplaced with a —NR^(4a)—C(O)— or —C(O)—NR^(4a)— moiety. Thus X isselected from —C₁alkylene-, —C₁alkylene-, —C₂alkylene-, —C₃alkylene-,—C₄alkylene-, —C₅alkylene-, —C₆alkylene-, —C₇alkylene-, —C₈alkylene,—C₉alkylene-, —C₁₀alkylene-, —C₁₁alkylene-, and —C₁₂alkylene-. R^(4a) isselected from H, —OH, and —C₁₋₄alkyl. In one embodiment, R^(4a) is H.

Each carbon atom in this C₁₋₁₂alkylene moiety may be substituted withone or more R^(4b) groups. R^(4b) is selected from—C₀₋₅alkylene-COOR^(4c), —C₁₋₆alkyl, —C₀₋₁alkylene-CONH₂,—C₁₋₂alkylene-OH, —C₀₋₃alkylene-C₃₋₇cycloalkyl, 1H-indol-3-yl, benzyl,and hydroxybenzyl, where R^(4c) is H or —C₁₋₄alkyl. In one embodiment,the carbon atoms in —C₁₋₂alkylene- are unsubstituted with R^(4b) groups.In another embodiment, 1 or 2 carbon atoms are substituted with one ortwo R^(4b) groups; and in one such embodiment, R^(4b) is —COOH, benzylor —C₁₋₆alkyl, including —C₁₋₃alkyl groups such as —CH₃ and —CH(CH₃)₂.

In addition, one —CH₂— moiety in X may be replaced with a group selectedfrom —C₃₋₈cycloalkylene- (for example, cyclohexylene), —CR^(4d)═CH—, and—CH═CR^(4d)—, where R^(4d) is selected from —CH₂-thiophene and phenyl.In one embodiment, none of the —CH₂-moieties are so replaced.

Each alkyl and each aryl in R^(4a), R^(4b), R^(4c), and R^(4d) may besubstituted with 1 to 7 fluoro atoms, and the term “alkyl” is intendedto include divalent alkylene groups such as that present in—C₀₋₅alkylene-COOR^(4c), for example. It is noted that the R^(4b) group,—C₀₋₃alkylene-C₃₋₇cycloalkyl, is intended to include a C₃₋₇cycloalkyllinked to the X —C₁₋₁₂alkylene- chain by a bond as well as aC₃₋₇cycloalkyl that is directly attached to the chain, as illustratedbelow:

In one embodiment, one to four —CH₂— moieties are replaced with—NR^(4a)—C(O)— or —C(O)—NR^(4a)— moieties; in another embodiment one—CH₂— moiety is replaced, examples of which include: —C(O)NH—, —NHC(O)—,and —CH₂—NHC(O)—. In one embodiment, X is C₁₋₆alkylene and 1, 2, 3, or4-CH₂— moieties are replaced with a —NR^(4a)—C(O)— or —C(O)—NR^(4a)—moiety; in another embodiment X is —C₁₋₃alkylene- and 1 or 2-CH₂—moieties are replaced. In one embodiment X is —C₁₋₂alkylene- and one—CH₂— moiety is replaced. When more than one —CH₂— moiety in—C₁₋₁₂alkylene- is replaced with a —NR^(4a)— C(O)— or —C(O)—NR^(4a)—moiety, the replaced moieties may be contiguous or non-contiguous.

Exemplary X groups include the following, which depict, examples whereone or more —CH₂— moieties are replaced with —NR^(4a)—C(O)— or—C(O)—NR^(4a)— moieties, examples where —CH₂— moieties are replaced witha group selected from —C₃₋₈cycloalkylene-, —CR^(4d)═CH—, and—CH═CR^(4d)—, as well as examples where carbon atoms in the—C₁₋₁₂alkylene- group are substituted with one or more R^(4b) groups:

—C₁alkylene- with one —CH₂— moiety replaced:

-   -   —C(O)NH—    -   —NHC(O)—

—C₂alkylene- with one —CH₂— moiety replaced:

-   -   —CH₂—NHC(O)—    -   —C(O)NH—CH₂—    -   —CH₂—C(O)NH—    -   —CH[CH(CH₃)₂]—C(O)NH—

—C₂alkylene- with two —CH₂— moieties replaced:

-   -   —C(O)NH—NHC(O)—    -   —CH═C(—CH₂-2-thiophene)-C(O)NH—

—C₃alkylene- with one —CH₂— moiety replaced:

-   -   —(CH₂)₂—NHC(O)—    -   —CH(CH₃)—CH₂—NHC(O)—    -   —CH[CH(CH₃)₂]-CH₂—NHC(O)—    -   —CH(COOH)—CH₂—NHC(O)—    -   —CH₂—CH(COOH)—NHC(O)—

—C₃alkylene- with two —CH₂— moieties replaced:

-   -   —NHC(O)—CH₂—NHC(O)—

—C₄alkylene- with one —CH₂— moiety replaced:

-   -   —(CH₂)₃—NHC(O)—    -   —C(O)NH—CH₂—CH(COOH)—CH₂

—C₄alkylene- with two —CH₂— moieties replaced:

-   -   —C(O)NH—CH(benzyl)-CH₂—NHC(O)—    -   —C(O)NH—CH(benzyl)-CH₂—C(O)NH—    -   —CH₂—NHC(O)—CH₂—NHC(O)—

—C₄alkylene- with three —CH₂— moieties replaced:

-   -   —CH₂—NHC(O)-cyclohexylene-NHC(O)—    -   —CH₂—N(OH)C(O)-cyclohexylene-NHC(O)—

—C₅alkylene- with two —CH₂— moieties replaced:

-   -   —CH₂—NHC(O)—CH₂—CH(COOH)—NHC(O)—    -   —CH₂—NHC(O)—(CH₂)₂—NHC(O)—    -   —C(O)NH—(CH₂)₂—C(O)N(OH)—CH₂    -   —C(O)NH—(CH₂)₂—CH(COOH)—NHC(O)—    -   —CH(COOH)—CH₂—NHC(O)—CH₂—NHC(O)—    -   —(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—

—C₆alkylene- with two —CH₂— moieties replaced:

-   -   —C(O)NH—(CH₂)₄—NHC(O)—    -   —CH₂—NHC(O)—(CH₂)₂—CH(COOH)—NHC(O)—    -   —C(O)NH—(CH₂)₃—CH(COOH)—NHC(O)—    -   —C₆alkylene- with three —CH₂— moieties replaced:    -   —C(O)NH—(CH₂)₂—NHC(O)—CH₂—NHC(O)—

—C₆alkylene- with four —CH₂— moieties replaced:

-   -   —C(O)NH—(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—    -   —C₇alkylene- with two —CH₂— moieties replaced:    -   —CH₂—NHC(O)—(CH₂)₄—NHC(O)—    -   —C(O)NH—(CH₂)₄—CH(COOH)—NHC(O)—

—C₇alkylene- with three —CH₂— moieties replaced:

-   -   —CH[CH(CH₃)₂]-C(O)NH—(CH₂)₂—NHC(O)—CH₂—NHC(O)—    -   —C₇alkylene- with four —CH₂— moieties replaced:    -   —CH₂—NHC(O)—(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—    -   —CH₂—C(O)NH—(CH₂)₂—NHC(O)-cyclohexylene-NHC(O)—    -   —C₈alkylene- with three —CH₂— moieties replaced:    -   —C(O)NH—(CH₂)₄—NHC(O)—CH₂—NHC(O)—

—C₈alkylene- with four —CH₂— moieties replaced:

-   -   —C(O)NH—(CH₂)₄—NHC(O)-cyclohexylene-NHC(O)—

—C₉alkylene- with two —CH₂— moieties replaced:

-   -   —CH₂—NHC(O)—(CH₂)₆—NHC(O)—

—C₉alkylene- with four —CH₂— moieties replaced:

-   -   —CH₂—NHC(O)—(CH₂)₄—NHC(O)-cyclohexylene-NHC(O)—

—C₁₀alkylene- with four —CH₂— moieties replaced:

-   -   —C(O)NH—(CH₂)₆—NHC(O)-cyclohexylene-NHC(O)—

—C₁₁alkylene- with three —CH₂— moieties replaced:

-   -   —CH(CH(CH₃)₂)—C(O)NH—(CH₂)₆—NHC(O)—CH₂—NHC(O)—

—C₁₁alkylene- with four —CH₂— moieties replaced:

-   -   —CH₂—NHC(O)—(CH₂)₆—NHC(O)-cyclohexylene-NHC(O)—        In one embodiment, X is selected from —C(O)NH—, —NHC(O)—, and        —CH₂—NHC(O)—.

R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f),—C₀₋₂alkylene-CHR^(5g)—COOH, —C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH,and —C₀₋₃alkylene-S—SR^(5j). Each alkyl and each aryl in R⁵ isoptionally substituted with 1 to 7 fluoro atoms, where the term “alkyl”is intended to include divalent alkylene groups such as those present in—C₀₋₃alkylene-SR^(5a) and —C₀₋₃alkylene-P(O)OR^(5e)R^(5f), for example.Each aryl and heteroaryl in R⁵ may be substituted with 1 to 3 —OH,—C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, -phenyl, —NO₂, —NH₂,—NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)₂ groups. Further, each of theaforementioned alkyl, alkenyl and alkynyl groups may be substituted with1 to 5 fluoro atoms. It is understood that when referring to “eachalkyl”, “each aryl”, and “each heteroaryl” in R⁵, the terms also includeany alkyl, aryl, and heteroaryl groups that might be present in theR^(a)-51, R^(5aa), R^(5ab), R^(5ba), R^(5bb), R^(5bc), R^(5ca), R^(5da),R^(5db), R^(5ea), R^(5eb), R^(5ec), R^(5fa), and R^(5fb) moieties (whichare defined below).

In one embodiment, R⁵ is —C₀₋₃alkylene-SR^(5a). R^(5a) is H or—C(O)—R^(5aa). The R^(5aa) group is R^(5aa) is —C₁₋₆alkyl,—C₀₋₆alkylene-C₃₋₇cycloalkyl, -aminoC₄₋₇cycloalkyl, —C₀₋₆alkylenearyl,—C₀₋₆alkyleneheteroaryl, —C₀₋₆alkylenemorpholine,—C₀₋₆alkylenepiperazine-CH₃, —C₀₋₆alkylenepiperidine,—C₀₋₆alkylenepiperidine-CH₃, —CH[N(R^(5ab))₂]-aa where aa is an aminoacid side chain, —C₀₋₆alkylene-CH[N(R^(5ab))₂]—R^(5ac), -2-pyrrolidine,-2-tetrahydrofuran, —C₀₋₆alkylenearyl-OR^(5ab), —O—C₀₋₆alkylenearyl,—C₁₋₂alkylene-OC(O)—C₁₋₆alkyl, —C₁₋₂alkylene-OC(O)—C₀₋₆alkylenearyl,—O—C₁₋₂alkylene-OC(O)O—C₁₋₆alkyl, —C₁₋₄alkylene-COOH, or -arylene-COOH.The R^(5ab) group is H or —C₁₋₆alkyl, and the R^(5ac) group is H,—C₁₋₆alkyl, —CH₂—C₃₋₇cycloalkyl or —COOH. In one specific embodiment,R^(5a) is H, for example, R⁵ may be —SH or —CH₂SH. In anotherembodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is —C₁₋₆alkyl.Exemplary —C₁₋₆alkyl groups include —CH₃, —CH₂CH₃, —CH(CH₃)₂,—(CH₂)₂CH₃, —C(CH₃)₃, and —CH₂CH(CH₃)₂. Thus, examples of R⁵ include—SC(O)CH₃, —CH₂SC(O)CH₃, —CH₂SC(O)CH₂CH₃, —CH₂SC(O)CH(CH₃)₂,CH₂SC(O)(CH₂)₂CH₃, and —CH₂SC(O)C(CH₃)₃, and —CH₂SC(O)CH₂CH(CH₃)₂. Inone embodiment, R^(5a) is selected from H and —C(O)—C₁₋₆alkyl.

In another embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa), is—C₀₋₆alkylene-C₃₋₇cycloalkyl. Exemplary C₃₋₇cycloalkyl groups includecyclopentyl and cyclohexyl. Thus, examples of R⁵ include—CH₂SC(O)-cyclopentyl, —CH₂SC(O)-cyclohexyl, and—CH₂SC(O)—CH₂-cyclopentyl.

In another embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa), is-aminoC₄₋₇cycloalkyl. Such examples of R⁵ include—CH₂SC(O)-aminocyclobutane, —CH₂SC(O)-aminocyclopentane, and—CH₂SC(O)-aminocyclohexane, depicted as:

In another embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—C₀₋₆alkylenearyl and the aryl is optionally substituted with 1 to 3substituents such as —O—C₁₋₆alkyl and —NH₂. Exemplary aryl groupsinclude phenyl and -phenyl-OCH₃. Thus, examples of R⁵ include—CH₂SC(O)-phenyl and —CH₂SC(O)-benzyl and with substituted aryl groupssuch as —CH₂SC(O)-phenyl-OCH₃, —CH₂SC(O)-2-aminophenyl,—CH₂SC(O)-3-aminophenyl, and —CH₂SC(O)-4-aminophenyl.

In yet another embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—C₀₋₆alkyleneheteroaryl. Exemplary heteroaryl groups include furanyl,thienyl and pyridinyl. Thus, examples of R⁵ include:—CH₂SC(O)-2-pyridine, —CH₂SC(O)-3-pyridine, and —CH₂SC(O)-4-pyridine.

In another embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—C₀₋₆alkylenemorpholine:

more particularly, —C₁₋₃alkylenemorpholine. Thus, examples of R⁵ include—CH₂S—C(O)CH₂-morpholin-4-yl, —CH₂S—C(O)(CH₂)₂-morpholin-4-yl, and—CH₂SC(O)(CH₂)₃— morpholin-4-yl. In another embodiment, R^(5a) is—C(O)—R^(5aa), where R^(5aa) is —C₀₋₆alkylenepiperazine-CH₃. Thus,examples of R⁵ include —CH₂SC(O)(CH₂)₂₋₄-methylpiperazin-1-yl.

In another embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—C₀₋₆alkylenepiperidine. Thus, examples of R⁵ include—CH₂SC(O)—CH₂-2-piperidin-1-yl. In another embodiment, R^(5a) is—C(O)—R^(5aa), where R^(5aa) is —C₀₋₆alkylenepiperidine-CH₃. Thus,examples of R⁵ include —CH₂SC(O)—CH₂-2-methylpiperidin-1-yl,—CH₂SC(O)—CH₂-3-methylpiperidin-1-yl, and—CH₂SC(O)(CH₂)₂₋₄-methylpiperazin-1-yl.

In one embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—CH[N(R^(5ab))₂]-aa where aa is an amino acid side chain. For example,the amino acid side chain could be —CH(CH₃)₂ (valine side chain),—CH₂CH(CH₃)₂ (leucine side chain), —CH(CH₃)CH₂CH₃ (isoleucine sidechain), —CH₂COOH (aspartic acid side chain), —(CH₂)₂COOH (glutamic acidside chain), —CH(OH)(CH₃) (threonine side chain), -benzyl (phenylalanineside chain), -4-hydroxybenzyl (tyrosine side chain), and —(CH₂)₂SCH₃(methionine side chain). Thus, other examples of R⁵ include—CH₂SC(O)CH(NH₂)—CH(CH₃)₂, —CH₂SC(O)CH(NH₂)—CH₂CH(CH₃)₂,—CH₂SC(O)CH(NH₂)—CH(CH₃)CH₂CH₃, —CH₂SC(O)CH(NH₂)—CH₂COOH,—CH₂SC(O)CH(NH₂)—(CH₂)₂COOH, —CH₂SC(O)CH(NH₂)—CH(OH)(CH₃),—CH₂SC(O)—CH(NH₂)-benzyl, —CH₂SC(O)CH(NH₂)-4-hydroxybenzyl,—CH₂SC(O)CH(NH₂)—(CH₂)₂SCH₃.

In one embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—C₀₋₆alkylene-CH[N(R^(5ab))₂]—R^(5ac) and R^(5ac) is H. Such examples ofR⁵ include —CH₂SC(O)CH₂N(CH₃)₂, —CH₂SC(O)(CH₂)₂N(CH₃)₂, and—CH₂SC(O)(CH₂)₃N(CH₃)₂. In another embodiment, R^(5a) is —C(O)—R^(5aa),where R^(5aa) is —C₀₋₆alkylene-CH[N(R^(5ab))₂]-R^(5ac) and R^(5ac) is—C₁₋₆alkyl. Such examples of R⁵ include —CH₂SC(O)CH(NH₂)—CH₂CH₃,—CH₂SC(O)CH(NH₂)—(CH₂)₂CH₃, —CH₂SC(O)CH(NH₂)—C(CH₃)₃, and—CH₂SC(O)—CH(NH₂)—(CH₂)₃CH₃. In another embodiment, R^(5a) is—C(O)—R^(5aa), where R^(5aa) is —C₀₋₆alkylene-CH[N(R^(5ab))₂]R^(5ac) andR^(5ac) is —CH₂—C₃₋₇cycloalkyl. Such examples of R⁵ includeCH₂SC(O)CH(NH₂)—CH₂-cyclobutyl and —CH₂SC(O)CH(NH₂)—CH₂-cyclohexyl. Inyet another embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—C₀₋₆alkylene-CH[N(R^(5ab))₂]—R^(5ac) and R^(5ac) is —COOH. Suchexamples of R⁵ include —CH₂SC(O)CH₂CH(NH₂)COOH and—CH₂SC(O)(CH₂)₂CH(NH₂)—COOH.

In yet another embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is-2-pyrrolidine or -2-tetrahydrofuran:

Thus, examples of R⁵ include —CH₂SC(O)-2-pyrrolidine and—CH₂SC(O)-tetrahydrofuran-2-yl.

In another embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—C₀₋₆alkylene-OR^(5ab). In one embodiment, R^(5ab) is H, such thatR^(5a) is —C(O)—C₀₋₆alkylene-OH. In another embodiment, R^(5ab) is—C₁₋₆alkyl, such that R^(5a) is C(O)—C₀₋₆alkylene-O—C₁₋₆alkyl, forexample, R⁵ may be —CH₂SC(O)—O—CH₂CH₃.

In another embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—O—C₀₋₆alkylenearyl. In yet another embodiment, R^(5a) is —C(O)—R^(5aa),where R^(5aa) is —C₁₋₂alkylene-OC(O)—C₁₋₆alkyl. One example of such anR⁵ group is —CH₂SC(O)CH₂—OC(O)CH₃. In another embodiment, R^(5a) is—C(O)—R^(5aa), where R^(5aa) is —C₁₋₂alkylene-OC(O)—C₀₋₆alkylenearyl. Inyet another embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—O—C₁₋₂alkylene-OC(O)O—C₁₋₆alkyl, for example, R⁵ may be—CH₂SC(O)OCH(CH₃)—OC(O)O—CH(CH₃)₂.

In another embodiment, R^(5a) is —C(O)—R^(5aa), where R^(5aa) is—C₁₋₄alkylene-COOH. Thus, examples of R⁵ include —CH₂SC(O)(CH₂)₂COOH. Inanother embodiment, R^(5a) is —C(O)—R^(a), where R^(5aa) is-arylene-COOH. Thus, examples of R⁵ include —CH₂SC(O)-3-carboxyphenyland —CH₂SC(O)-4-carboxyphenyl.

In one embodiment, R⁵ is —C₀₋₃alkylene-C(O)NR^(5b)R^(5c). The R^(5e)moiety is H, —OH, —OC(O)R^(5ba), —CH₂COOH, —O-benzyl, -pyridyl, or—OC(S)NR^(5bb)R^(5bc). R^(5ba) is H, —C₁₋₆alkyl, aryl, —OCH₂-aryl (forexample, —OCH₂-phenyl), —CH₂O-aryl (for example, —CH₂O-phenyl), or—NR^(5bb)R^(5bc). The R^(5bb) and R^(5bc) moieties are independentlyselected from H and —C₁₋₄alkyl. In one embodiment, R^(5b) is —OH or—OC(O)R^(5ba), where —R^(5ba) is —C₁₋₆alkyl. R^(5c) is H, —C₁₋₆alkyl, or—C(O)R^(5ca). R^(5ca) is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, aryl, orheteroaryl. In one particular embodiment, R^(5c) is H. In anotherembodiment, R^(5b) is —OH and R^(5c) is H, for example, R⁵ may be—C(O)NH(OH) or —CH₂C(O)NH(OH). In another embodiment, R^(5b) is—OC(O)R^(5ba), where —R^(5ba) is —C₁₋₆alkyl and R^(5c) is H, forexample, R⁵ may be —C(O)N[OC(O)CH₃]H or —C(O)N[OC(O)C(CH₃)₃]H. In stillanother embodiment, both R^(5b) and R^(5c) are H, for example, R⁵ may be—C(O)NH₂. In another embodiment, R^(5b) is —CH₂COOH and R^(5c) is H, forexample, R⁵ may be —C(O)NH(CH₂COOH). In yet another embodiment, R^(5b)is —OC(O)R^(5ba), where —R^(5ba) is —O—CH₂-aryl or —CH₂—O-aryl, forexample, R⁵ may be —CH₂—C(O)NH[OC(O)OCH₂-phenyl] and—CH₂—C(O)N[OC(O)CH₂O-phenyl]H. In another embodiment, R^(5b) is—OC(S)NR^(5bb)R^(5bc), where R^(5bb) and R^(5bc) are both —C₁₋₄alkyl,for example, R^(5b) may be —O—C(S)N(CH₃)₂. In another embodiment, R^(5b)is —OC(S)NR^(5bb)R^(5bc) and R^(5c) is H, for example, R⁵ may be—CH₂—C(O)N[OC(S)N(CH₃)₂]H.

In one embodiment, R⁵ is —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d). R^(5d) is H,—C₁₋₄alkyl, —C₀₋₃alkylenearyl, —NR^(5da)R^(5db), —CH₂SH, or—O—C₁₋₆alkyl. The R^(5da) and R^(5db) moieties are independentlyselected from H and —C₁₋₄alkyl. In another embodiment, R^(5b) is —OH andR^(5d) is H, for example, R⁵ may be —CH₂—N(OH)C(O)H. In anotherembodiment, R^(5b) is —OH and R^(5d) is —C₁₋₄alkyl, for example, R⁵ maybe —CH₂—N(OH)C(O)CH₃.

In another embodiment, R^(5b) is H and R^(5d) is —CH₂SH, for example, R⁵may be —NHC(O)CH₂SH or —CH₂NHC(O)—CH₂SH.

In yet another embodiment, R⁵ is —NH—C₀₋₁alkylene-P(O)(OR^(5e))₂. TheR^(5e) moiety is H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl,—C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl, —CH(CH₃)—O—C(O)R^(5ea),

The R^(5ea) group is —O—C₁₋₆alkyl, —O—C₃₋₇cycloalkyl, —NR^(5eb)R^(5ec),or —CH(NH₂)CH₂COOCH₃. R^(5eb) and R^(5ec) are independently selectedfrom H, —C₁₋₄alkyl, and —C₁₋₃alkylenearyl (for example, benzyl). R^(5eb)and R^(5ec) may also be taken together to form —(CH₂)₃₋₆—. In oneembodiment, R^(5e) is H, for example, R⁵ may be —NH—CH₂—P(O)(OH)₂.

In one embodiment, R⁵ is —C₀₋₃alkylene-P(O)OR^(5e)R^(5f). The R^(5f)moiety is H, —C₁₋₄alkyl, —C₀₋₃alkylenearyl,—C₁₋₃alkylene-NR^(5fa)R^(5fb), or—C₁₋₃alkylene(aryl)-C₀₋₃alkylene-NR^(5fa)R^(5fb). The R^(5fa) andR^(5fb) groups are independently selected from H and —C₁₋₄alkyl. In oneembodiment, R^(5e) is H, for example, R⁵ may be—C₀₋₃alkylene-P(O)(OH)R^(5f).

In one embodiment, R^(5e) is —C₀₋₂alkylene-CHR^(5g) —COOH. The R^(5g)moiety is H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl, or —CH₂—O—(CH₂)₂—OCH₃. Inone embodiment, R^(5g) is —CH₂—O—(CH₂)₂—OCH₃, for example R⁵ may be—CH₂—CH—[CH₂—O—(CH₂)₂—OCH₃]—COOH. In another embodiment, R^(5g) is H,for example R⁵ may be —CH₂COOH.

In one embodiment, R⁵ is —C₀₋₃alkylene-C(O)NR^(5h) —CHR^(5i)—COOH. TheR^(5h) moiety is H or —C₁₋₄alkyl. The R^(5i) moiety is H, —C₁₋₄alkyl, or—C₀₋₃alkylenearyl. In one embodiment, R^(5h) is H and R^(5i) is—C₀₋₃alkylenearyl, and the aryl is optionally substituted with 1 to 3substituents such as —OH, for example, R⁵ may be—C(O)NH—CH(CH₂-phenyl-OH)(COOH).

In another embodiment, R⁵ is —C₀₋₃alkylene-S—SR^(5j), and R^(5j) isselected from —C₁₋₆alkyl, aryl, and —CH₂CH(NH₂)COOH. Examples of such R⁵groups include —C₀₋₃alkylene-S—S—CH₃, —C₀₋₃alkylene-S—S-phenyl, and—C₀₋₃alkylene-S—S—CH₂CH(NH₂)—COOH.

R⁶ is selected from —C₁₋₆alkyl, —CH₂—O—(CH₂)₂OCH₃,—C₁₋₆alkylene-O—C₁₋₆alkyl, —C₀₋₃alkylenearyl, —C₀₋₃alkyleneheteroaryl,and —C₀₋₃alkylene-C₃₋₇cycloalkyl. In one particular embodiment, R⁶ isselected from —C₁₋₆alkyl, —C₀₋₃alkylenearyl, and—C₀₋₃alkylene-C₃₋₇cycloalkyl. In one particular embodiment, R⁶ isselected from —C₁₋₆alkyl, —C₀₋₃alkylenearyl, and—C₀₋₃alkylene-C₃₋₇cycloalkyl. Each alkyl and each aryl in R⁶ isoptionally substituted with 1 to 7 fluoro atoms, where the term “alkyl”is intended to include divalent alkylene groups such as those present in—C₁₋₆alkylene-O—C₁₋₆alkyl and —C₀₋₃alkylene-C₃₋₇cycloalkyl, for example.In addition, each aryl and heteroaryl in R⁶ may be substituted with 1 to3 —OH, —C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo, —O—C₁₋₆alkyl,—S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, -phenyl, —NO₂, —NH₂,—NH—C₁₋₆alkyl, or —N(C₁₋₆alkyl)₂ groups. Further, each of theaforementioned alkyl, alkenyl and alkynyl groups may be substituted with1 to 5 fluoro atoms.

In one embodiment, R⁶ is —C₁₋₆alkyl, for example, —CH₃, —CH₂CH₃,—CH(CH₃)₂, —(CH₂)₂CH₃, —(CH₂)₃CH₃, —(CH₂)₂CH(CH₃)₂, —CH(CH₃)CH₂CH₃,—CH₂CH(CH₃)₂, —CH₂C(CH₃)₃, and —(CH₂)₄CH₃. As noted above, each alkyl inR⁶ is optionally substituted with 1 to 7 fluoro atoms. Examples of suchfluoro-substituted R⁶ groups include —(CH₂)₂CF₃ and —(CH₂)₃CF₃.

In another embodiment, R⁶ is —CH₂O(CH₂)₂OCH₃. In still another oneembodiment, R⁶ is —C₁₋₆alkylene-O—C₁₋₆alkyl, for example, —OCH₃ and—CH₂OCH₃.

In one embodiment, R⁶ is —C₀₋₃alkylenearyl, for example, phenyl, benzyl,—CH₂-biphenyl, —(CH₂)₂-phenyl and —CH₂-naphthalen-1-yl. The aryl may besubstituted with 1 to 3 substituents. Examples of mono-substituted R⁶aryl groups include: methylbenzyl such as 4-methylbenzyl;fluoro-substituted alkylbenzyl groups such as 2-trifluoromethylbenzyl;chlorobenzyl such as 2-chlorobenzyl, 3-chlorobenzyl, and 4-chlorobenzyl;fluorobenzyl such as 2-fluorobenzyl, 3-fluorobenzyl, and 4-fluorobenzyl;fluorophenyl; bromobenzyl such as 4-bromobenzyl; iodobenzyl;-benzyl-CF₃, 2-trifluoromethyl-benzyl; -benzyl-CN; and -benzyl-NO₂.Examples of di-substituted R⁶ aryl groups include: di-chlorobenzyl suchas 2,4-dichlorobenzyl; and di-fluorobenzyl such as 3,5-difluorobenzyl.Each aryl may also be substituted with 1 to 7 fluoro atoms. Thus, otherexamples of R⁶ include penta-fluorobenzyl.

In one embodiment, R⁶ is —C₀₋₃alkyleneheteroaryl, for example,—CH₂-pyridyl, —CH₂-furanyl, —CH₂-thienyl, and —CH₂-thiophenyl such as—CH₂-thiophen-2-yl. In another embodiment, R⁶ is—C₀₋₃alkylene-C₃₋₇cycloalkyl, for example, —CH₂-cyclopropyl,cyclopentyl, —CH₂-cyclopentyl, and —CH₂-cyclohexyl.

R⁷ is H or is taken together with R⁶ to form —C₃₋₈cycloalkyl. In oneembodiment, R⁷ is H. In another embodiment, R⁷ is taken together with R⁶to form —C₃₋₈cycloalkyl, for example cyclopentyl.

One particular embodiment of the invention provides for an activecompound of formula I where Ar**—COOH represents Ar—R¹ and R⁵ is—C₀₋₃alkylene-SH. One corresponding prodrug (prodrug A) can contain athioester linkage, which can be cleaved in vivo to form the —COOH(R¹)and —C₀₋₃alkylene-SH(R⁵) moieties. Another corresponding prodrug(prodrug B, where Z is —C₁₋₆alkylene, optionally substituted with one ormore moieties such as hydroxyl, phenyl, carboxyl, and so forth),contains both an ester and a thioester group, which can be similarlycleaved in vivo, but which also releases a physiologically acceptableacid such as α-hydroxy acid (Z is —CH₂—), β-hydroxy acid (Z is—(CH₂)₂—), (R)-2-hydroxypropionic or lactic acid (Z is —CH(CH₃)—),(R)-hydroxyphenyl acetic or mandelic acid (Z is —CH(phenyl)-), salicylicacid (Z is -phenylene-), 2,3-dihydroxysuccinic or tartaric acid (Z is—CH[CH(OH)(COOH)]—), citric acid (Z is —C[CH₂COOH]₂—), hydroxy bis- andhydroxy-tris acids, and so forth.

Yet another corresponding prodrug (prodrug C) is a dimer form of prodrugA, thus containing two thioester linkages, which can both be cleaved invivo to form two active moieties, each containing the —COOH(R¹) and—C₀₋₃alkylene-SH(R⁵) moieties.

Another embodiment of the invention provides for an active compound offormula I where R⁵ is —C₀₋₃alkylene-SH, and the prodrug (prodrug D) is adimer form of the compound:

Examples of prodrug D include:

For R^(1a)=t-butyl, MS m/z: [M+H⁺] calcd for C₇₈H₈₄N₆O₆S₂, 1,265.59.found 1265.8. For R^(1a)═H, MS m/z: [M+H⁺] calcd for C₇₀H₆₈N₆O₆S₂,1,153.46. found 1153.6.

In one particular embodiment, the compound of formula I is the speciesembodied in formula Ia:

where r, n, X, R¹⁻³, and R⁵⁻⁷ are as defined for formula I. In oneparticular embodiment of the species of formula Ia: r is 1; R¹ is—COOR^(1a), —SO₂NHR^(1d), or tetrazol-5-yl; R^(1a) is H, —C₁₋₆alkyl,—C₁₋₃alkylenearyl, —CH(C₁₋₄alkyl)OC(O)R^(1aa), —C₀₋₆alkylenemorpholine,or

R^(1aa) is —O—C₁₋₆alkyl or —O—C₃₋₇cycloalkyl; R^(1c) is —C₁₋₆alkyl,—C₀₋₆alkylene-O—R^(1ca), —C₁₋₅alkylene-NR^(1cb)R^(1cc), or—C₀₋₄alkylenearyl; R^(1ca) is H, —C₁₋₆alkyl, or—C₁₋₆alkylene-O—C₁₋₆alkyl; R^(1cb) and R^(1cc) are independentlyselected from H and —C₁₋₆alkyl, or are taken together as—(CH₂)₂—O—(CH₂)₂— or —(CH₂)₂—N[C(O)CH₃]-(CH₂)₂—; R^(1d) is —C(O)R^(1c)or —C(O)NHR^(1c); n is 0 or 1; R² is halo, —C₁₋₆alkyl, or—C₀₋₅alkylene-OR^(2b), where R^(2b) is H; R³ is —C₁₋₁₀alkyl or—C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b), where R^(3b) is —C₁₋₆alkyl; R⁵ is—C₀₋₃alkylene-SR^(5a), —C₀₋₃alkylene-C(O)NR^(5b)R^(5c), or—C₀₋₃alkylene-NR^(5b)C(O)R^(5d); R^(1a) is H or —C(O)—R^(5aa); R^(5aa)is —C₁₋₆alkyl, —C₀₋₆alkylene-C₃₋₇cycloalkyl, -aminoC₄₋₇cycloalkyl,—C₀₋₆alkylenearyl, —C₀₋₆alkyleneheteroaryl, —C₀₋₆alkylenemorpholine,—C₀₋₆alkylene-piperazine-CH₃, —C₀₋₆alkylenepiperidine,—C₀₋₆alkylenepiperidine-CH₃, —CH[N(R^(5ab))₂]-aa where aa is an aminoacid side chain, —C₀₋₆alkylene-CH[N(R^(5ab))₂]—R^(5ac), -2-pyrrolidine,-2-tetrahydrofuran, —C₀₋₆alkylene-OR^(5ab),—C₁₋₂alkylene-OC(O)—C₁₋₆alkyl, —C₁₋₄alkylene-COOH, or -arylene-COOH;R^(5ab) is independently H or —C₁₋₆alkyl; R^(5ac) is H, —C₁₋₆alkyl,—CH₂—C₃₋₇cycloalkyl or —COOH; R^(5b) is —OH; R^(5c) is H; R^(5d) is H or—C₁₋₄alkyl; R⁶ is —C₁₋₆alkyl, —C₀₋₃alkylenearyl,—C₀₋₃alkyleneheteroaryl, or —C₀₋₃alkylene-C₃₋₇cycloalkyl; and R⁷ is H;each alkyl in R² is optionally substituted with 1 to 7 fluoro atoms;each ring in Ar and each aryl and heteroaryl in R¹ and R⁵⁻⁶ isoptionally substituted with 1 to 2 substituents independently selectedfrom —C₁₋₆alkyl, halo, —O—C₁₋₆alkyl, and —NH₂, wherein each alkyl isoptionally substituted with 1 to 5 fluoro atoms.

When X is selected from —CH₂—NHC(O)—, —NHC(O)—, and —C(O)NH—, thecompounds of formula Ia may be depicted as formulas Ia-1, Ia-2, andIa-3, respectively:

where r, n, R¹⁻³, and R⁵⁻⁶ are as defined for formula I; andpharmaceutically acceptable salts thereof.

In one particular embodiment of the species of formula Ia-1 and Ia-b: ris 1; R¹ is —COOR^(1a) or tetrazol-5-yl, where R^(1a) is H or—C₁₋₆alkyl; n is 1; R² is —C₁₋₆alkyl; R³ is —C₁₋₁₀alkyl; R⁵ is—C₀₋₃alkylene-SR^(5a); R^(5a) is H or —C(O)—R^(5aa), where R^(5aa) is—C₁₋₆alkyl; R⁶ is —C₁₋₆alkyl, —C₀₋₃alkylenearyl, or—C₀₋₃alkylene-C₃₋₇cycloalkyl; and R⁷ is H.

In one particular embodiment of the species of formula Ia-3: r is 1; R¹is —COOR^(a), —SO₂NHR^(1d), or tetrazol-5-yl; R^(1a) is H, —C₁₋₆alkyl,—C₁₋₃alkylenearyl, —CH(C₁₋₄alkyl)O—C(O)R^(1aa), —C₀₋₆alkylenemorpholine,or

R^(1aa) is —O—C₁₋₆alkyl or —O—C₃₋₇cycloalkyl; R^(1c) is —C₁₋₆alkyl,—C₀₋₆alkylene-O—R^(1ac), —C₁₋₅alkylene-NR cbR^(1cc), or—C₀₋₄alkylenearyl; Rca is H, —C₁₋₆alkyl or —C₁₋₆alkylene-O—C₁₋₆alkyl;R^(1cb) and R^(1cc) are independently selected from H and —C₁₋₆alkyl, orare taken together as —(CH₂)₂—O—(CH₂)₂— or —(CH₂)₂—N[C(O)CH₃]-(CH₂)₂—;R^(1d) is —C(O)R^(1c) or —C(O)NHR^(1c); n is 0 or 1; R² is halo,—C₁₋₆alkyl, or —C₀₋₅alkylene-OR^(2b) where R^(2b) is H; R³ is—C₁₋₁₀alkyl or —C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b), where R^(3b) is—C₁₋₆alkyl; R⁵ is —C₀₋₃alkylene-SR^(5a), —C₀₋₃alkylene-C(O)NR^(5b)R^(5c)or —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d); R^(5a) is H or —C(O)—R^(5aa);R^(5aa) is —C₁₋₆alkyl, —C₀₋₆alkylene-C₃₋₇cycloalkyl,-aminoC₄₋₇cycloalkyl, —C₀₋₆alkylenearyl, —C₀₋₆alkyleneheteroaryl,—C₀₋₆alkylenemorpholine, —C₀₋₆alkylenepiperazine-CH₃,—C₀₋₆alkylenepiperidine, —C₀₋₆alkylenepiperidine-CH₃, —CH[N(Rab)₂]-aawhere aa is an amino acid side chain,—C₀₋₆alkylene-CH[N(R^(5ab))₂]—R^(5ac), -2-pyrrolidine,-2-tetrahydrofuran, —C₁₋₂alkylene-OC(O)—C₁₋₆alkyl, —C₁₋₄alkylene-COOH,or -arylene-COOH; R^(5ab) is independently H or —C₁₋₆alkyl; R^(5ac) isH, —C₁₋₆alkyl, —CH₂—C₃₋₇cycloalkyl or —COOH; R^(5b) is —OH; R^(5c) is H;R^(5d) is H or —C₁₋₄alkyl; R⁶ is —C₁₋₆alkyl, —C₀₋₃alkylenearyl,—C₀₋₃alkyleneheteroaryl, or —C₀₋₃alkylene-C₃₋₇cycloalkyl; and R⁷ is H;each alkyl in R² is optionally substituted with 1 to 7 fluoro atoms;each ring in Ar and each aryl and heteroaryl in R¹ and R⁵⁻⁶ isoptionally substituted with 1 to 2 substituents independently selectedfrom —C₁₋₆alkyl, halo, —O—C₁₋₆alkyl, and —NH₂, wherein each alkyl isoptionally substituted with 1 to 5 fluoro atoms.

In another embodiment of the species of formula Ia-3: r is 1; R¹ is—SO₂NHR^(1d); R^(1c) is —C₁₋₆alkyl, —C₀₋₆alkylene-O-—R^(1ca), or—C₁₋₆alkylenearyl; R^(1ca) is H, —C₁₋₆alkyl, or—C₁₋₆alkylene-O—C₁₋₆alkyl; R^(1cb) and R^(1cc) are independentlyselected from H and —C₁₋₆alkyl, or are taken together as—(CH₂)₂—O—(CH₂)₂— or —(CH₂)₂—N[C(O)CH₃]-(CH₂)₂—; R^(1d) is —C(O)R^(1c)or —C(O)NHR^(1c); n is 1; R² is —C₁₋₆alkyl; R³ is —C₁₋₁₀alkyl; R⁵ is—C₀₋₃alkylene-SR^(5a) or —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d); R^(5a) is Hor —C(O)—R^(5aa); R^(5aa) is —C₁₋₆alkyl; R^(5b) is —OH; R^(5d) is H; R⁶is —C₁₋₆alkyl or —C₀₋₃alkylenearyl; and R⁷ is H.

In one particular embodiment, the compound of formula I is the speciesembodied in formula Ib:

In one particular embodiment of the species of formula Ib: r is 1; R¹ is—COOR^(1a), where R^(1a) is H or —C₁₋₆alkyl; n is 1; R² is —C₁₋₆alkyl;R³ is —C₁₋₁₀alkyl; X is —CH₂—NHC(O)—, —NHC(O)—, or —C(O)NH—; R⁵ is—C₀₋₃alkylene-SR^(5a), —C₀₋₃alkylene-C(O)NR^(5b)R^(5c), or—C₀₋₃alkylene-NR^(5b)—C(O)R^(5d); R^(5a) is H or —C(O)—R^(5aa); R^(5aa),is —C₁₋₆alkyl; R^(5b) is —OH; R^(5c) is H; R^(5d) is H or —C₁₋₄alkyl; R⁶is —C₁₋₆alkyl, —C₀₋₃alkylenearyl, or —C₀₋₃alkylene-C₃₋₇cycloalkyl; R⁷ isH; the alkyl in R⁶ is optionally substituted with 1 to 7 fluoro atoms;and the phenyl ring is optionally substituted with 1 halo atom.

When X is selected from —CH₂—NHC(O)—, —NHC(O)—, and —C(O)N—H—, thecompounds of formula Ib may be depicted as formulas Ib-1, ib-2, andib-3, respectively:

where r, n, R¹⁻³, and R⁵⁻⁶ are as defined for formula I; andpharmaceutically acceptable salts thereof.

In one particular embodiment of the species of formula Ib-1: r is 1; R¹is —COOR^(1a), where R^(1a) is H or —C₁₋₆alkyl; n is 1; R² is—C₁₋₆alkyl; R³ is —C₁₋₁₀alkyl; R⁵ is —C₀₋₃alkylene-SR^(5a) or—C₀₋₃alkylene-C(O)NR^(5b)R^(5c); R^(5a) is H or —C(O)—R^(5aa); R^(a) is—C₁₋₆alkyl; R^(5b) is —OH; R^(5c) is H; R⁶ is —C₁₋₆alkyl,—C₀₋₃alkylenearyl, or —C₀₋₃alkylene-C₃₋₇cycloalkyl; R⁷ is H; the alkylin R⁶ is optionally substituted with 1 to 7 fluoro atoms; and the phenylring is optionally substituted with 1 halo atom.

In one particular embodiment of the species of formula Ib-2: r is 1; R¹is —COOR^(1a), where R^(1a) is H or —C₁₋₆alkyl; n is 1; R² is—C₁₋₆alkyl; R³ is —C₁₋₁₀alkyl; R⁵ is —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), or —C₀₋₃alkylene-NR^(5b); R^(5a) is Hor —C(O)—R^(5aa); R^(5aa), is —C₁₋₆alkyl; R^(5b) is —OH; R^(5c) is H;R^(5d) is H or —C₁₋₄alkyl; R⁶ is —C₁₋₆alkyl, —C₀₋₃alkylenearyl, or—C₀₋₃alkylene-C₃₋₇cycloalkyl; R⁷ is H; the alkyl in R⁶ is optionallysubstituted with 1 to 7 fluoro atoms; and the phenyl ring is optionallysubstituted with 1 halo atom.

In one particular embodiment of the species of formula Ib-3: r is 1; R¹is —COOR^(1a), where R^(1a) is H or —C₁₋₆alkyl; n is 1; R² is—C₁₋₆alkyl; R³ is —C₁₋₁₀alkyl; R⁵ is —C₀₋₃alkylene-SR^(5a)—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), or —C₀₋₃alkylene-NR^(5b)C(O)R^(5d);R^(5a) is H or —C(O)—R^(5aa); R^(5aa) is —C₁₋₆alkyl; R^(5b) is —OH;R^(5c) is H; R^(5d) is H or —C₁₋₄alkyl; R⁶ is —C₁₋₆alkyl or—C₀₋₃alkylenearyl; and R⁷ is H.

In one particular embodiment, the compound of formula I is the speciesembodied in formula Ic:

In one particular embodiment of the species of formula Ic: r is 1; R¹ is—COOR^(1a) or —SO₂NHR^(1d); R^(1a) is H or —C₁₋₆alkyl; R^(1d) is—C(O)R^(1c); R^(1c) is —C₁₋₆alkyl; n is 1; R² is —C₁₋₆alkyl; R³ is—C₁₋₁₀alkyl; X is —C(O)NH—; R⁵ is —C₀₋₃alkylene-SR^(5a); R^(5a) is H or—C(O)—R^(5aa); R^(5aa) is —C₁₋₆alkyl; R⁶ is —C₁₋₆alkyl or—C₀₋₃alkylenearyl; and R⁷ is H.

In one particular embodiment, the compound of formula I is the speciesembodied in formula Id:

In one particular embodiment of the species of formula Id: r is 1; R¹ is—COOR^(1a), where R^(1a) is H or —C₁₋₆alkyl; n is 1; R² is —C₁₋₆alkyl;R³ is —C₁₋₁₀alkyl; X is —C(O)NH—; R⁵ is —C₀₋₃alkylene-SR^(5a); R^(5a) isH or —C(O)—R^(5aa); R^(5aa) is —C₁₋₆alkyl; R⁶ is —C₁₋₆alkyl or—C₀₋₃alkylenearyl; and R⁷ is H.

In one particular embodiment, r is 1; and Ar is an aryl group selectedfrom:

where Ar is optionally substituted with one fluoro or chloro atom.

In one particular embodiment, r is 1; and n is 0, or n is 1 and R² is atthe 4 position. In another aspect, these embodiments have formula Ia,Ia-1, Ia-2, Ia-3, Ib, Ib-1, Ib-2, Ib-3, Ic or Id.

In another particular embodiment, R¹ is selected from —COOH,—NHSO₂R^(1b), —SO₂NHR^(1d), —SO₂OH, —C(O)NH—SO₂R^(1c), —P(O)(OH)₂, —CN,—O—CH(R^(1e))—COOH, tetrazol-5-yl,

where R^(1b), R^(1c), R^(1d), and R^(1e), are as defined for formula I.In one particular embodiment, R¹ is selected from —COOR^(1a),—SO₂NHR^(1d), and tetrazol-5-yl. In another embodiment, R¹ is selectedfrom —COOH, —SO₂NHR^(1d) (for example —SO₂NHC(O)—C₁₋₆alkyl), andtetrazol-5-yl. In another aspect, these embodiments have formula Ia,Ia-1, Ia-2, Ia-3, Ib, Ib-1, Ib-2, Ib-3, Ic or Id.

In one particular embodiment, R¹ is —COOR^(1a), where R^(1a) is—C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl,—CH(C₁₋₄alkyl)OC(O)R^(1aa), —C₀₋₆alkylenemorpholine,

where R^(1aa) is as defined for formula I. In one aspect of theinvention, these compounds may find particular utility as prodrugs or asintermediates in the synthetic procedures described herein. In oneparticular embodiment, R¹ is —COOR^(1a) and R^(1a) is —C₁₋₆alkyl. Inanother aspect, these embodiments have formula Ia, Ia-1, Ia-2, Ia-3, Ib,Ib-1, Ib-2, Ib-3, Ic or Id.

In one particular embodiment, R¹ is selected from —COOR^(1a) andtetrazol-5-yl, where R^(1a) is H or —C₁₋₆alkyl. In another aspect, thisembodiment has formula Ia, Ia-1, Ia-2, Ia-3, Ib, Ib-1, Ib-2, Ib-3, Ic orId.

In one embodiment, R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f),—C₀₋₂alkylene-CHR^(5g)—COOH, and—C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH; where R^(5a) is H, R^(5b) is—OH, R^(5c) is H, R^(5d) is H, R^(5e) is H; and R^(5f), R^(5g), R^(5h),R^(5i) are as defined for formula I. More particularly, in oneembodiment, R⁵ is selected from —C₀₋₁alkylene-SH,—C₀₋₁alkylene-C(O)—N(OH)H, and —C₀₋₃alkylene-N(OH)—C(O)H. In anotherembodiment, R⁵ is selected from —C₀₋₃alkylene-SR^(5a) and—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), where R^(5a) is H and R^(5b) is —OH. Inone particular embodiment, R^(5c) is H. In another aspect, theseembodiments have formula Ia, Ia-1, Ia-2, Ia-3, Ib, Ib-1, Ib-2, Ib-3, Icor Id.

In yet another embodiment, R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f), and—C₀₋₃alkylene-S—SR^(5j); where R^(5a) is —C(O)—R^(5aa); R^(5b) is H,—OC(O)R^(5ba), —CH₂COOH, —O-benzyl, -pyridyl, or —OC(S)NR^(5bb)R^(5bc);R^(5e) is —C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl,—C₃₋₇cycloalkyl, —CH(CH₃)—O—C(O)R^(5ea),

and where R^(5aa), R^(5ba), R^(5bb), R^(5bc), R^(5c), R^(5d), R^(5ea),R^(5f), and R^(5j) are as defined for formula I. In one aspect of theinvention, these compounds may find particular utility as prodrugs or asintermediates in the synthetic procedures described herein. In anotheraspect, these embodiments have formula Ia, Ia-1, Ia-2, Ia-3, Ib, Ib-1,Ib-2, Ib-3, Ic or Id.

In one particular embodiment, R⁵ is selected from —C₀₋₃alkylene-SR^(5a)and —C₀₋₃alkylene-C(O)NR^(5b)R^(5c); where R^(5a) is selected from H and—C(O)—C₁₋₆alkyl; R^(5b) is selected from H, —OH, and —OC(O)—C₁₋₆alkyl;and R^(5c) is selected from H and —C₁₋₆alkyl. In another aspect, thisembodiment has formula Ia, Ia-1, Ia-2, Ia-3, Ib, Ib-1, Ib-2, Ib-3, Ic orId.

In another embodiment, R¹ is selected from —COOR^(1a) where R^(1a) is H,—NHSO₂R^(1b), —SO₂NHR^(1d), —SO₂OH, —C(O)NH—SO₂R^(1c), —P(O)(OH)₂, —CN,—O—CH(R^(1e))—COOH, tetrazol-5-yl,

R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f),—C₀₋₂alkylene-CHR^(5g)—COOH, and—C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH; R^(5a) is H; R^(5b) is —OH;R^(5c) is H; R^(5d) is H; R^(5e) is H; and R^(1b), R^(1c), R^(1d),R^(1e), R^(5f), R^(5g), R^(5h), R^(5i) areas defined for formula I. Inone particular embodiment, R¹ is selected from —COOH, —SO₂NHR^(1d), andtetrazol-5-yl; and R⁵ is selected from —C₀₋₃alkylene-SH, and—C₀₋₃alkylene-C(O)N(OH)H. In another aspect, these embodiments haveformula Ia, Ia-1, Ia-2, Ia-3, Ib, Ib-1, Ib-2, Ib-3, Ic or Id.

In another embodiment, R¹ is —COOR^(1a), where R^(1a) is selected from—C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl,—CH(C₁₋₄alkyl)OC(O)R^(1aa), —C₀₋₆alkylenemorpholine,

R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f), and—C₀₋₃alkylene-S—SR^(5j); where R^(5a) is —C(O)—R^(5aa); R^(5b) is H,—OC(O)R^(5ba), —CH₂COOH, —O-benzyl, -pyridyl, or —OC(S)NR^(5bb)R^(5bc);R^(5e) is —C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl,—C₃₋₇cycloalkyl, —CH(CH₃)—O—C(O)R^(5ea),

where R^(1aa), R^(5aa), R^(5ba), R^(5bb), R^(5bc), R^(5c), R^(5d),R^(5ea), R^(5f), and R^(5j) are as defined for formula I. In anotheraspect, this embodiment has formula Ia, Ia-1, Ia-2, Ia-3, Ib, Ib-1,Ib-2, Ib-3, Ic or Id.

In another particular embodiment, R¹ is selected from —COOR^(1a) whereR^(1a) is H, —NHSO₂R^(1b), SO₂NHR^(1d), —SO₂OH, —C(O)NH—SO₂R^(1c),—P(O)(OH)₂, —CN, —O—CH(R^(1e))—COOH, tetrazol-5-yl,

R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f), and—C₀₋₃alkylene-S—SR^(5j); where R^(5a) is —C(O)—R^(5aa); R^(5b) is H,—OC(O)R^(5ba), —CH₂COOH, —O-benzyl, -pyridyl, or —OC(S)NR^(5bb)R^(5bc);R^(5e) is —C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl,—C₃₋₇cycloalkyl, —CH(CH₃)—O—C(O)R^(5ea),

and where R^(1b), R^(1c), R^(1d), R^(1e), R^(5aa), R^(5ba), R^(5bb),R^(5bc), R^(5c), R^(5d), R^(5ea), R^(5f), and R^(5j) are as defined forformula I. In another aspect, this embodiment has formula Ia, Ia-1,Ia-2, Ia-3, Ib, Ib-1, Ib-2, Ib-3, Ic or Id.

In another embodiment, R¹ is —COOR^(1a), where R^(1a) is selected from—C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl,—CH(C₁₋₄alkyl)OC(O)R^(1aa), —C₀₋₆alkylenemorpholine,

R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d),—NH—C₀₋₁alkylene-P(O)(OR^(5e))₂, —C₀₋₃alkylene-P(O)OR^(5e)R^(5f),—C₀₋₂alkylene-CHR^(5g)—COOH, and—C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—COOH; R^(5a) is H; R^(5b) is —OH;R^(5c) is H; R^(5d) is H; R^(5e) is H; and R^(1aa), R^(5f), R^(5g),R^(5h), R^(5i) are as defined for formula I. In another aspect, thisembodiment has formula Ia, Ia-1, Ia-2, Ia-3, Ib, Ib-1, Ib-2, Ib-3, Ic orId.

A particular group of compounds of formula I are those disclosed in U.S.Provisional Application No. 60/933,207, filed on Jun. 5, 2007. Thisgroup includes compounds of formula I′:

wherein: r′ is 0, 1 or 2; Ar′ is an aryl group selected from:

R¹′ is selected from —COOR^(1a)′, —NHSO₂—C₁₋₆alkyl, —NHSO₂aryl,—NHSO₂NHC(O)—C₁₋₆alkyl, —NHSO₂NHC(O)-aryl, —SO₂NHC(O)—C₁₋₆alkyl,—SO₂NHC(O)-aryl, —SO₂NHC(O)NH—C₁₋₆alkyl, —SO₂NHC(O)NH-aryl, —SO₂OH,—SO₂NH₂, —SO₂NH—C₁₋₆alkyl, —SO₂NH-aryl, —C(O)NH—SO₂—C₁₋₆alkyl,—C(O)NH—SO₂-aryl, —P(O)(OH)₂, —CN, —OCH(CH₃)—COOH, —OCH(aryl)-COOH,tetrazol-5-yl,

where R^(1a)′ is selected from H, —C₁₋₆alkyl, benzyl,—C₁₋₃alkyleneheteroaryl, cycloalkyl, —CH(CH₃)OC(O)R^(1b)′,

R^(1b)′ is selected from —O—C₁₋₆alkyl, —O-cycloalkyl, —NR^(1c)′R^(1d)′,—CH(NH₂)CH₂COOCH₃; and R^(1c)′ and R^(1d)′ are independently selectedfrom H, —C₁₋₆alkyl, and benzyl, or are taken together as —(CH₂)₃₋₆—;

n′ is 0, 1, 2 or 3; R²′ is selected from —CH₂OH, halo, —NO₂, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₃₋₆cycloalkyl, —CN, —C(O)R^(2a)′,—C₀₋₅alkylene-OR^(2b)′, —C₀₋₅alkylene-NR^(2c)′R^(2d)′,—C₀₋₃alkylenearyl, and —C₀₋₃alkyleneheteroaryl; where R^(2a)′ isselected from H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl, —C₀₋₃alkylenephenyl,—OR^(2b)′, and —NR^(2c)′R^(2d)′; R^(2b)′ is selected from H, —C₁₋₆alkyl,—C₃₋₆cycloalkyl, and —C₀₋₁alkylenephenyl; and R^(2c)′ and R^(2d)′ areindependently selected from H, —C₁₋₄alkyl, and —C₀₋₁alkylenephenyl;

R³′ is selected from —C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₃₋₁₀alkynyl,—C₀₋₃alkylene-C₃₋₇cycloalkyl, —C₂₋₃alkenylene-C₃₋₇cycloalkyl,—C₂₋₃alkynylene-C₃₋₇cycloalkyl,—C₀₋₅alkylene-NR^(3a)′—C₀₋₅alkylene-R^(3b)′,C₀₋₅alkylene-O—C₁₋₅alkylene-R^(3b)′,—C₁₋₅alkylene-S—C₁₋₅alkylene-R^(3b)′, and —C₀₋₃alkylenearyl; whereR^(3a)′ is selected from H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl, and—C₀₋₁alkylenephenyl; and R^(3b)′ is selected from H, —C₁₋₆alkyl,—C₃₋₆cycloalkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, and phenyl;

X′ is —C₁₋₁₂alkylene-, where at least one —CH₂— moiety in the alkyleneis replaced with a —NR^(4a), —C(O)— or —C(O)—NR^(4a)′-moiety, whereR^(4a)′ is selected from H, —OH, and —C₁₋₄alkyl;

R⁵′ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)′R^(5c)′, —C₀₋₃alkylene-NR^(5b)′—C(O)R^(5d)′,—C₀₋₁alkylene-NHC(O)CH₂SH, —NH—C₀₋₁alkylene-P(O)(OR^(5e)′)₂,—C₀₋₃alkylene-P(O)OR^(5e)′R^(5f)′, —C₀₋₂alkylene-CHR^(5g)′-COOH and—C₀₋₃alkylene-C(O)NR^(5h)′—CHR^(5i)′—COOH; where R^(5a), is selectedfrom H, —C(O)—C₁₋₆alkyl, —C(O)—C₀₋₆alkylene-C₃₋₇cycloalkyl,—C(O)—C₀₋₆alkylenearyl, —C(O)—C₀₋₆alkyleneheteroaryl, —C(O)—OC₁₋₆alkyl,—C(O)—OC₀₋₆alkylenearyl, —C₁₋₂alkylene-OC(O)—C₁₋₆alkyl,—C₁₋₂alkylene-OC(O)—C₀₋₆alkylenearyl, and—C₁₋₂alkylene-OC(O)—OC₁₋₆alkyl; R^(5b)′ is selected from H, —OH,—OC(O)—C₁₋₆alkyl, —CH₂COOH, —O-benzyl, -pyridyl, —OC(O)OCH₂-phenyl,—OC(O)CH₂O-phenyl, —OC(O)N(CH₃)₂, and —OC(S)N(CH₃)₂; R^(5c)′ is selectedfrom H, —C₁₋₆alkyl, and —C(O)—R^(5c)″, where R^(5c)″ is selected from—C₁₋₆alkyl, —C₃₋₇cycloalkyl, aryl, and heteroaryl; R^(5d)′ is selectedfrom H, —C₁₋₄alkyl, —C₀₋₃alkylenearyl, —NR^(5d)″R^(5d)′″, and—O—C₁₋₆alkyl, where R^(5d)″, and R^(5d)′″ are independently selectedfrom H and —C₁₋₄alkyl; R^(5e)′ is selected from H, —C₁₋₆alkyl, benzyl,—C₁₋₃alkyleneheteroaryl, cycloalkyl, —CH(CH₃)OC(O)R^(5e)″,

where R^(5e)″ is selected from —O—C₁₋₆alkyl, —O-cycloalkyl,—NR^(5e)′″R^(5e)″″, and —CH(H₂)CH₂COOCH₃, and where R^(5e)′″ andR^(5e)″″ are independently selected from H, —C₁₋₆alkyl, and benzyl, orare taken together as —(CH₂)₃₋₆—; R^(5f)′ is selected from H,—C₁₋₄alkyl, —C₀₋₃alkylenearyl, —C₁₋₃alkylene-NR^(5f)′R^(5f)′″, and—C₁₋₃alkylene(aryl)-C₀₋₃alkylene-NR^(5f)′R^(5f)′″, where R^(5f)″ andR^(5f)′″ are independently selected from H and —C₁₋₄alkyl; R^(5g)′ isselected from H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl, and —CH₂—O—(CH₂)₂—OCH₃;R^(5h)′ is selected from H and —C₁₋₄alkyl; and R^(5i)′ is selected fromH, —C₁₋₄alkyl, and —C₀₋₃alkylenearyl;

R⁶′ is selected from —C₁₋₆alkyl, —CH₂O(CH₂)₂OCH₃,—C₁₋₆alkylene-O—C₁₋₆alkyl, —C₀₋₃alkylenearyl, —C₀₋₃alkyleneheteroaryl,and —C₀₋₃alkylene-C₃₋₇cycloalkyl; and

R⁷′ is H or is taken together with R⁶′ to form —C₃₋₈cycloalkyl; wherein:each —CH₂— group in —(CH₂)_(r′)— is optionally substituted with 1 or 2substituents independently selected from —C₁₋₄alkyl and fluoro; eachcarbon atom in the alkylene moiety in X′ is optionally substituted withone or more R^(4b)′ groups and one —CH₂— moiety in X′ may be replacedwith —C₄₋₈cycloalkylene-; wherein R^(4b)′ is selected from—C₀₋₅alkylene-COOH, —C₁₋₆alkyl, —C₀₋₁alkylene-CONH₂, —C₁₋₂alkylene-OH,—C₀₋₃alkylene-C₃₋₇cycloalkyl, and benzyl; each alkyl and each aryl inR¹′⁻³′, R^(4a)′^(-4b)′, and R⁵′⁻⁶′ is optionally substituted with 1 to 7fluoro atoms; each ring in Ar′ and each aryl in R¹′⁻³′ and R⁵′⁻⁶′ isoptionally substituted with 1 to 3 substituents independently selectedfrom —OH, —C₁₋₆alkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo,—O—C₁₋₆alkyl, —S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, -phenyl,—NO₂, —NH₂, —NH—C₁₋₆alkyl and —N(C₁₋₆alkyl)₂, wherein each alkyl,alkenyl and alkynyl is optionally substituted with 1 to 5 fluoro atoms;and pharmaceutically acceptable salts thereof.

In addition, particular compounds of formula I that are of interestinclude those set forth in the Examples below, as well as thepharmaceutically acceptable salts thereof.

Definitions

When describing the compounds, compositions, methods and processes ofthe invention, the following terms have the following meanings unlessotherwise indicated. Additionally, as used herein, the singular forms“a,” “an,” and “the” include the corresponding plural forms unless thecontext of use clearly dictates otherwise. The terms “comprising”,“including,” and “having” are intended to be inclusive and mean thatthere may be additional elements other than the listed elements.

The term “pharmaceutically acceptable” refers to a material that is notbiologically or otherwise undesirable. For example, the term“pharmaceutically acceptable carrier” refers to a material that can beincorporated into a composition and administered to a patient withoutcausing undesirable biological effects or interacting in a deleteriousmanner with other components of the composition. Such pharmaceuticallyacceptable materials typically have met the required standards oftoxicological and manufacturing testing, and include those materialsidentified as suitable inactive ingredients by the U.S. Food and DrugAdministration.

The term “pharmaceutically acceptable salt” means a salt prepared from abase or an acid which is acceptable for administration to a patient,such as a mammal (for example, salts having acceptable mammalian safetyfor a given dosage regime). However, it is understood that the saltscovered by the invention are not required to be pharmaceuticallyacceptable salts, such as salts of intermediate compounds that are notintended for administration to a patient. Pharmaceutically acceptablesalts can be derived from pharmaceutically acceptable inorganic ororganic bases and from pharmaceutically acceptable inorganic or organicacids. In addition, when a compound of formula I contains both a basicmoiety, such as an amine, pyridine or imidazole, and an acidic moietysuch as a carboxylic acid or tetrazole, zwitterions may be formed andare included within the term “salt” as used herein. Salts derived frompharmaceutically acceptable inorganic bases include ammonium, calcium,copper, ferric, ferrous, lithium, magnesium, manganic, manganous,potassium, sodium, and zinc salts, and the like. Salts derived frompharmaceutically acceptable organic bases include salts of primary,secondary and tertiary amines, including substituted amines, cyclicamines, naturally-occurring amines and the like, such as arginine,betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine,2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine,ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine,glucosamine, histidine, hydrabamine, isopropylamine, lysine,methylglucamine, morpholine, piperazine, piperidine, polyamine resins,procaine, purines, theobromine, triethylamine, trimethylamine,tripropylamine, tromethamine and the like. Salts derived frompharmaceutically acceptable inorganic acids include salts of boric,carbonic, hydrohalic (hydrobromic, hydrochloric, hydrofluoric orhydroiodic), nitric, phosphoric, sulfamic and sulfuric acids. Saltsderived from pharmaceutically acceptable organic acids include salts ofaliphatic hydroxyl acids (for example, citric, gluconic, glycolic,lactic, lactobionic, malic, and tartaric acids), aliphaticmonocarboxylic acids (for example, acetic, butyric, formic, propionicand trifluoroacetic acids), amino acids (for example, aspartic andglutamic acids), aromatic carboxylic acids (for example, benzoic,p-chlorobenzoic, diphenylacetic, gentisic, hippuric, and triphenylaceticacids), aromatic hydroxyl acids (for example, o-hydroxybenzoic,p-hydroxybenzoic, 1-hydroxynaphthalene-2-carboxylic and3-hydroxynaphthalene-2-carboxylic acids), ascorbic, dicarboxylic acids(for example, fumaric, maleic, oxalic and succinic acids), glucoronic,mandelic, mucic, nicotinic, orotic, pamoic, pantothenic, sulfonic acids(for example, benzenesulfonic, camphosulfonic, edisylic, ethanesulfonic,isethionic, methanesulfonic, naphthalenesulfonic,naphthalene-1,5-disulfonic, naphthalene-2,6-disulfonic andp-toluenesulfonic acids), xinafoic acid, and the like.

As used herein, the term “prodrug” is intended to mean an inactive (orsignificantly less active) precursor of a drug that is converted intoits active form in the body under physiological conditions, for example,by normal metabolic processes. The term is also intended to includecertain protected derivatives of compounds of formula I that may be madeprior to a final deprotection stage. Such compounds may not possesspharmacological activity at AT₁ and/or NEP, but may be administeredorally or parenterally and thereafter metabolized in the body to formcompounds of the invention which are pharmacologically active at AT₁and/or NEP. Thus, all protected derivatives and prodrugs of compoundsformula I are included within the scope of the invention. Prodrugs ofcompounds of formula I having a free carboxyl, sulfhydryl or hydroxygroup can be readily synthesized by techniques that are well known inthe art. These prodrug derivatives are then converted by solvolysis orunder physiological conditions to be the free carboxyl, sulfhydryland/or hydroxy compounds. Exemplary prodrugs include: esters includingC₁₋₆alkylesters and aryl-C₁₋₆alkylesters, carbonate esters, hemi-esters,phosphate esters, nitro esters, sulfate esters, sulfoxides, amides,carbamates, azo-compounds, phosphamides, glycosides, ethers, acetals,ketals, and disulfides. In one embodiment, the compounds of formula Ihave a free sulfhydryl or a free carboxyl and the prodrug is an esterderivative thereof, i.e., the prodrug is a thioester such as —SC(O)CH₃or an ester such as —C(O)OCH₃.

The term “solvate” means a complex or aggregate formed by one or moremolecules of a solute, for example, a compound of formula I or apharmaceutically acceptable salt thereof, and one or more molecules of asolvent. Such solvates are typically crystalline solids having asubstantially fixed molar ratio of solute and solvent. Representativesolvents include, by way of example, water, methanol, ethanol,isopropanol, acetic acid and the like. When the solvent is water, thesolvate formed is a hydrate.

The term “therapeutically effective amount” means an amount sufficientto effect treatment when administered to a patient in need thereof, thatis, the amount of drug needed to obtain the desired therapeutic effect.For example, a therapeutically effective amount for treatinghypertension could be the amount of drug needed to reduce blood pressureor the amount of drug needed to maintain normal blood pressure. On theother hand, the term “effective amount” means an amount sufficient toobtain a desired result, which may not necessary be a therapeuticresult. For example, when studying a system comprising an AT₁ receptor,an “effective amount” may be the amount needed to antagonize thereceptor.

The term “treating” or “treatment” as used herein means the treating ortreatment of a disease or medical condition (such as hypertension) in apatient, such as a mammal (particularly a human) that includes: (a)preventing the disease or medical condition from occurring, that is,prophylactic treatment of a patient; (b) ameliorating the disease ormedical condition such as by eliminating or causing regression of thedisease or medical condition in a patient; (c) suppressing the diseaseor medical condition such as by slowing or arresting the development ofthe disease or medical condition in a patient; or (d) alleviating thesymptoms of the disease or medical condition in a patient. For example,the term “treating hypertension” would include preventing hypertensionfrom occurring, ameliorating hypertension, suppressing hypertension, andalleviating the symptoms of hypertension (for example, lowering bloodpressure). The term “patient” is intended to include those mammals, suchas humans, that are in need of treatment or disease prevention, or thatare presently being treated for disease prevention or treatment of aspecific disease or medical condition. The term “patient” also includestest subjects in which compounds of the invention are being evaluated ortest subjects are being used in a assay, for example an animal model.

The term “alkyl” means a monovalent saturated hydrocarbon group whichmay be linear or branched. Unless otherwise defined, such alkyl groupstypically contain from 1 to 10 carbon atoms and include, for example,—C₁₋₄alkyl, —C₁₋₆alkyl, and —C₁₋₁₀alkyl. Representative alkyl groupsinclude, by way of example, methyl, ethyl, n-propyl, isopropyl, n-butyl,s-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl,n-nonyl, n-decyl and the like.

When a specific number of carbon atoms is intended for a particular termused herein, the number of carbon atoms is shown preceding the term assubscript. For example, the term “—C₁₋₆alkyl” means an alkyl grouphaving from 1 to 6 carbon atoms, and the term “—C₃₋₆cycloalkyl” means acycloalkyl group having from 3 to 6 carbon atoms, where the carbon atomsare in any acceptable configuration.

The term “alkylene” means a divalent saturated hydrocarbon group thatmay be linear or branched. Unless otherwise defined, such alkylenegroups typically contain from 0 to 12 carbon atoms and include, forexample, —CO— alkylene-, —C₀₋₂alkylene-, —C₀₋₃alkylene-, —C₀₋₅alkylene-,—C₀₋₆alkylene-, —C₁₋₂alkylene- and —C₁₋₁₂alkylene-. Representativealkylene groups include, by way of example, methylene, ethane-1,2-diyl(“ethylene”), propane-1,2-diyl, propane-1,3-diyl, butane-1,4-diyl,pentane-1,5-diyl and the like. It is understood that when the alkyleneterm include zero carbons such as —C₀₋₁alkylene- or —C₀₋₅alkylene-, suchterms are intended to include a single bond.

The term “alkylthio” means a monovalent group of the formula —S-alkyl,where alkyl is as defined herein. Unless otherwise defined, suchalkylthio groups typically contain from 1 to 10 carbon atoms andinclude, for example, —S—C₁₋₄alkyl and —S—C₁₋₆alkyl. Representativealkylthio groups include, by way of example, ethylthio, propylthio,isopropylthio, butylthio, s-butylthio and t-butylthio.

The term “alkenyl” means a monovalent unsaturated hydrocarbon groupwhich may be linear or branched and which has at least one, andtypically 1, 2 or 3, carbon-carbon double bonds. Unless otherwisedefined, such alkenyl groups typically contain from 2 to 10 carbon atomsand include, for example, —C₂₋₄alkenyl and —C₂₋₁₀alkenyl. Representativealkenyl groups include, by way of example, ethenyl, n-propenyl,isopropenyl, n-but-2-enyl, n-hex-3-enyl and the like. The term“alkenylene” means a divalent alkenyl group, and includes groups such as—C₂₋₃alkenylene-.

The term “alkoxy” means a monovalent group of the formula —O-alkyl,where alkyl is as defined herein. Unless otherwise defined, such alkoxygroups typically contain from 1 to 10 carbon atoms and include, forexample, —O—C₁₋₄alkyl and —O—C₁₋₆alkyl. Representative alkoxy groupsinclude, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy,n-butoxy, sec-butoxy, isobutoxy, t-butoxy and the like.

The term “alkynyl” means a monovalent unsaturated hydrocarbon groupwhich may be linear or branched and which has at least one, andtypically 1, 2 or 3, carbon-carbon triple bonds. Unless otherwisedefined, such alkynyl groups typically contain from 2 to 10 carbon atomsand include, for example, —C₂₋₄alkynyl and —C₃₋₁₀alkynyl. Representativealkynyl groups include, by way of example, ethynyl, n-propynyl,n-but-2-ynyl, n-hex-3-ynyl and the like. The term “alkynylene” means adivalent alkynyl group and includes groups such as —C₂₋₃alkynylene-.

Amino acid residues are often designated as —C(O)—CHR—NH—, where the Rmoiety is referred to as the “amino acid side chain.” Thus, for theamino acid valine, HO—C(O)—CH[—CH(CH₃)₂]—NH₂, the side chain is—CH(CH₃)₂. Ther term “amino acid side chain” is intended to include sidechains of the twenty common naturally occurring amino acids: alanine,arginine, asparagine, aspartic acid, cysteine, glutamic acid, glutamine,glycine, histidine, isoleucine, leucine, lysine, methionine,phenylalanine, proline, serine, threonine, tryptophan, tyrosine, andvaline. Of particular interest are the side chains of non-polar aminoacids such as isoleucine, leucine, and valine.

The term “aryl” means a monovalent aromatic hydrocarbon having a singlering (for example, phenyl) or fused rings. Fused ring systems includethose that are fully unsaturated (for example, naphthalene) as well asthose that are partially unsaturated (for example,1,2,3,4-tetrahydronaphthalene). Unless otherwise defined, such arylgroups typically contain from 6 to 10 carbon ring atoms and include, forexample, —C₆₋₁₀aryl. Representative aryl groups include, by way ofexample, phenyl and naphthalene-1-yl, naphthalene-2-yl, and the like.The term “arylene” means a divalent aryl group such as phenylene.

The term “cycloalkyl” means a monovalent saturated carbocyclichydrocarbon group. Unless otherwise defined, such cycloalkyl groupstypically contain from 3 to 10 carbon atoms and include, for example,—C₃₋₅cycloalkyl, —C₃₋₆cycloalkyl and —C₃₋₇cycloalkyl. Representativecycloalkyl groups include, by way of example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl and the like. The term “cycloalkylene” means adivalent aryl group such as —C₄₋₈cycloalkylene.

The term “halo” means fluoro, chloro, bromo and iodo.

The term “heteroaryl” means a monovalent aromatic group having a singlering or two fused rings and containing in the ring(s) at least oneheteroatom (typically 1 to 3) selected from nitrogen, oxygen or sulfur.Unless otherwise defined, such heteroaryl groups typically contain from5 to 10 total ring atoms and include, for example, —C₂₋₉heteroaryl.Representative heteroaryl groups include, by way of example, monovalentspecies of pyrrole, imidazole, thiazole, oxazole, furan, thiophene,triazole, pyrazole, isoxazole, isothiazole, pyridine, pyrazine,pyridazine, pyrimidine, triazine, indole, benzofuran, benzothiophene,benzoimidazole, benzthiazole, quinoline, isoquinoline, quinazoline,quinoxaline and the like, where the point of attachment is at anyavailable carbon or nitrogen ring atom.

The term “optionally substituted” means that group in question may beunsubstituted or it may be substituted one or several times, such as 1to 3 times or 1 to 5 times. For example, an alkyl group that is“optionally substituted” with 1 to 5 fluoro atoms, may be unsubstituted,or it may contain 1, 2, 3, 4, or 5 fluoro atoms.

The term “protected derivatives thereof” means a derivative of thespecified compound in which one or more functional groups of thecompound are protected or blocked from undergoing undesired reactionswith a protecting or blocking group. Functional groups that may beprotected include, by way of example, carboxy groups, amino groups,hydroxyl groups, thiol groups, carbonyl groups and the like.Representative protecting groups for carboxy groups include esters (suchas a p-methoxybenzyl ester), amides and hydrazides; for amino groups,carbamates (such as t-butoxycarbonyl) and amides; for hydroxyl groups,ethers and esters; for thiol groups, thioethers and thioesters; forcarbonyl groups, acetals and ketals; and the like. Such protectinggroups are well-known to those skilled in the art and are described, forexample, in T. W. Greene and G. M. Wuts, Protecting Groups in OrganicSynthesis, Third Edition, Wiley, New York, 1999, and references citedtherein.

All other terms used herein are intended to have their ordinary meaningas understood by those of ordinary skill in the art to which theypertain.

General Synthetic Procedures

Compounds of the invention can be prepared from readily availablestarting materials using the following general methods, the proceduresset forth in the Examples, or by using other methods, reagents, andstarting materials that are known to those of ordinary skill in the art.Although the following procedures may illustrate a particular embodimentof the invention, it is understood that other embodiments of theinvention can be similarly prepared using the same or similar methods orby using other methods, reagents and starting materials known to thoseof ordinary skill in the art. It will also be appreciated that wheretypical or preferred process conditions (for example, reactiontemperatures, times, mole ratios of reactants, solvents, pressures,etc.) are given, other process conditions can also be used unlessotherwise stated. While optimum reaction conditions will typically varydepending on various reaction parameters such as the particularreactants, solvents and quantities used, those of ordinary skill in theart can readily determine suitable reaction conditions using routineoptimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary or desired to preventcertain functional groups from undergoing undesired reactions. Thechoice of a suitable protecting group for a particular functional groupas well as suitable conditions and reagents for protection anddeprotection of such functional groups are well-known in the art.Protecting groups other than those illustrated in the proceduresdescribed herein may be used, if desired. For example, numerousprotecting groups, and their introduction and removal, are described inT. W. Greene and G. M. Wuts, Protecting Groups in Organic Synthesis,supra. More specifically, the following abbreviations and reagents areused in the schemes presented below:

P¹ represents an “amino-protecting group,” a term used herein to mean aprotecting group suitable for preventing undesired reactions at an aminogroup. Representative amino-protecting groups include, but are notlimited to, t-butoxycarbonyl (BOC), trityl (Tr), benzyloxycarbonyl(Cbz), 9-fluorenylmethoxycarbonyl (Fmoc), formyl, trimethylsilyl (TMS),t-butyldimethylsilyl (TBDMS), and the like. Standard deprotectiontechniques are used to remove the P¹ group. For example, deprotection ofthe N—BOC groups can use reagents such as TFA in DCM or HCl in1,4-dioxane, while the Cbz group can be removed by employing catalytichydrogenation conditions such as H₂ (1 atm), 10% Pd/C in an alcoholicsolvent.

P² represents a “carboxy-protecting group,” a term used herein to mean aprotecting group suitable for preventing undesired reactions at acarboxy group. Representative carboxy-protecting groups include, but arenot limited to, methyl, ethyl, t-butyl, benzyl (Bn), p-methoxybenzyl(PMB), 9-fluoroenylmethyl (Fm), trimethylsilyl (TMS),t-butyldimethylsilyl (TBDMS), diphenylmethyl (benzhydryl, DPM) and thelike. Standard deprotection techniques and reagents are used to removethe P² group, and may vary depending upon which group is used. Forexample, NaOH is commonly used when P² is methyl, an acid such as TFA orHCl is commonly used when P² is t-butyl, and catalytic hydrogenationcondition such as H₂ (1 atm) and 10% Pd/C in an alcoholic solvent(“H₂/Pd/C”) may also be used when P² is benzyl.

P³ represents a “thiol-protecting group,” a term used herein to mean aprotecting group suitable for preventing undesired reactions at a thiolgroup. Representative thiol-protecting groups include, but are notlimited to, ethers, esters such as —C(O)CH₃, and the like. Standarddeprotection techniques and reagents such as NaOH, primary alkylamines,and hydrazine, may be used to remove the P³ group.

P⁴ represents a “tetrazole-protecting group,” a term used herein to meana protecting group suitable for preventing undesired reactions at atetrazole group. Representative tetrazole-protecting groups include, butare not limited to trityl and diphenylmethyl. Standard deprotectiontechniques and reagents such as TFA in DCM or HCl in 1,4-dioxane areused to remove the P⁴ group.

P⁵ represents a “hydroxyl-protecting group,” a term used herein to meana protecting group suitable for preventing undesired reactions at ahydroxyl group. Representative hydroxyl-protecting groups include, butare not limited to alkyl groups such as t-butyl, silyl groups includingtriC₁₋₆alkylsilyl groups, such as trimethylsilyl (TMS), triethylsilyl(TES), and tert-butyldimethylsilyl (TBDMS); esters (acyl groups)including C₁₋₆alkanoyl groups, such as formyl, acetyl, and pivaloyl, andaromatic acyl groups such as benzoyl; arylmethyl groups such as benzyl(Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), and diphenylmethyl(benzhydryl, DPM); and the like. Standard deprotection techniques andreagents are used to remove the P⁵ group, and may vary depending uponwhich group is used. For example, H₂/Pd/C is commonly used when P⁵ isbenzyl, while NaOH is commonly used when P⁵ is an acyl group.

P⁶ represents a “sulfonamide-protecting group,” a term used herein tomean a protecting group suitable for preventing undesired reactions at asulfonamide group. Representative sulfonamide-protecting groups include,but are not limited to t-butyl and acyl groups. Exemplary acyl groupsinclude aliphatic lower acyl groups such as the formyl, acetyl,phenylacetyl, butyryl, isobutyryl, valeryl, isovaleryl and pivaloylgroups, and aromatic acyl groups such as the benzoyl and4-acetoxybenzoyl. Standard deprotection techniques and reagents are usedto remove the P⁶ group, and may vary depending upon which group is used.For example, HCl is commonly used when P⁶ is t-butyl, while NaOH iscommonly used when P⁶ is an acyl group.

P⁷ represents a “phosphate-protecting group or phosphinate-protectinggroup,” a term used herein to mean a protecting group suitable forpreventing undesired reactions at a phosphate or phosphinate group.Representative phosphate and phosphinate protecting groups include, butare not limited to C₁₋₄alkyls, aryl (for example, phenyl) andsubstituted aryls (for example, chlorophenyl and methylphenyl). Theprotected group can be represented by —P(O)(OR)₂, where R is a groupsuch as a C₁₋₆alkyl or phenyl. Standard deprotection techniques andreagents such as TMS-I/2,6-lutidine (MeCN), and H₂/Pd/C are used toremove the P⁷ group such as ethyl, and benzyl, respectively.

In addition, L is used to designate a “leaving group,” a term usedherein to mean a functional group or atom which can be displaced byanother functional group or atom in a substitution reaction, such as anucleophilic substitution reaction. By way of example, representativeleaving groups include chloro, bromo and iodo groups; sulfonic estergroups, such as mesylate, triflate, tosylate, brosylate, nosylate andthe like; and acyloxy groups, such as acetoxy, trifluoroacetoxy and thelike.

Suitable bases for use in these schemes include, by way of illustrationand not limitation, potassium carbonate, calcium carbonate, sodiumcarbonate, triethylamine, pyridine, 1,8-diazabicyclo-[5.4.0]undec-7-ene(DBU), N,N-diisopropylethylamine (DIPEA), sodium hydroxide, potassiumhydroxide, potassium t-butoxide, and metal hydrides.

Suitable inert diluents or solvents for use in these schemes include, byway of illustration and not limitation, tetrahydrofuran (THF),acetonitrile (MeCN), N,N-dimethylformamide (DMF), dimethyl sulfoxide(DMSO), toluene, dichloromethane (DCM), chloroform (CHCl₃), carbontetrachloride (CCl₄), 1,4-dioxane, methanol, ethanol, water, and thelike.

Suitable carboxylic acid/amine coupling reagents includebenzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate(BOP), benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate(PyBOP), O-(7-azabenzotriazol-1-yl-N,N,N′,N′tetramethyluroniumhexafluorophosphate (HATU), N,N′-dicyclohexylcarbodiimide (DCC),N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDC),carbonyldiimidazole (CDI), and the like. Coupling reactions areconducted in an inert diluent in the presence of a base, and areperformed under conventional amide bond-forming conditions.

All reactions are typically conducted at a temperature within the rangeof about −78° C. to 100° C., for example at room temperature. Reactionsmay be monitored by use of thin layer chromatography (TLC), highperformance liquid chromatography (HPLC), and/or LCMS until completion.Reactions may be complete in minutes, or may take hours, typically from1-2 hours and up to 48 hours. Upon completion, the resulting mixture orreaction product may be further treated in order to obtain the desiredproduct. For example, the resulting mixture or reaction product may besubjected to one or more of the following procedures: concentrating orpartitioning (for example, between EtOAc and water or between 5% THF inEtOAc and 1M phosphoric acid); extraction (for example, with EtOAc,CHCl₃, DCM, HCl); washing (for example, with saturated aqueous NaCl,saturated NaHCO₃, Na₂CO₃ (5%), CHCl₃ or 1M NaOH); drying (for example,over MgSO₄, over Na₂SO₄, or in vacuo); filtering; crystallizing (forexample, from EtOAc and hexane); and/or being concentrated (for example,in vacuo).

By way of illustration, compounds of formula I, as well as their salts,solvates, and prodrugs can be prepared by one or more of the followingexemplary processes.

Scheme I Peptide Coupling Reaction and Optional Deprotection

The X moiety contains one or more amide groups, and therefore thecompounds of the invention are typically formed by a coupling reactionunder conventional amide bond-forming conditions, followed by adeprotection step if needed. In Scheme I, the A and B moieties couple toform X, and the sum of a and b is in the range of 0 to 11. Thus, onemoiety comprises an amine group and one moiety comprises a carboxylicacid group, i.e., A is —NH₂ and B is —COOH or A is —COOH and B is —NH₂.

For example, to synthesize a compound of formula I where X is —CONH—, Awould be —COOH and B would be —NH₂. Similarly, A as —NH₂ and B as —COOHwould couple to form —NHCO— as the X moiety. A and B can be readilymodified if a longer X is desired, whether it contains an alkyleneportion or additional amide groups. For example, A as —CH₂NH₂ and B as—COOH would couple to form —CH₂NHCO— as the X moiety.

It is understood that the carbon atoms in the —(CH₂) a and —(CH₂)_(b)groups make up the “X” linker. Therefore, these carbon atoms may besubstituted with one or more R^(4b) groups. Furthermore, one —CH₂— groupin the —(CH₂)_(a) or the —(CH₂)_(b) group may be replaced with a—C₃₋₈cycloalkylene-, —CR^(4d)═CH—, or —CH═CR^(4d)— group.

Ar* represents Ar—R¹*, where R¹* may represent R¹ as defined herein, ora protected form of R¹ (e.g., -tetrazol-5-yl-P⁴ or —C(O)O—P² such as—C(O)O—C₁₋₆alkyl), or a precursor of R¹ (e.g., —CN that is thenconverted to tetrazole, or nitro that is then converted to amino fromwhich the desired R¹ is prepared). R⁵* represents R⁵ as defined herein,or a protected form of R⁵. Therefore, when R¹* represents R¹ and R⁵*represents R⁵, the reaction is complete after the coupling step.

On the other hand, when R¹* represents a protected form of R¹ and/or R⁵*represents a protected form of R⁵, a subsequent global or sequentialdeprotection step would yield the non-protected compound. Similarly,when R¹* represents a precursor of R¹, a subsequent conversion stepwould yield the desired compound. Reagents and conditions for thedeprotection vary with the nature of protecting groups in the compound.Typical deprotection conditions when R⁵* represents C₀₋₃alkylene-S—P³,include treating the compound with NaOH in an alcoholic solvent at 0° C.or room temperature to yield the non-protected compound. Typicaldeprotection conditions when R¹* represents C(O)O—P² where P² refers tot-butyl include treating the compound with TFA in DCM at roomtemperature to yield the non-protected compound. Thus, one method ofpreparing compounds of the invention involves coupling compound (1) and(2), with an optional deprotection step when R¹* is a protected form ofR¹ and/or R⁵* is a protected form of R⁵, thus forming a compound offormula I or a pharmaceutically acceptable salt thereof.

Examples of compound (1) include:3-(2′-t-butoxycarbonylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid; and4-(6-aminomethyl-4-methyl-2-propylbenzoimidazol-1-ylmethyl)-2-fluorobenzoicacid methyl ester. Examples of compound (2) include:(R)-1-benzyl-2-hydroxycarbamoylethyl)carbamic acid;(R)-2-((R)-2-amino-3-phenylpropyldisulfanyl)-1-benzylethylamine;(S)-2-acetylsulfanyl-4-methyl-pentanoic acid;2-acetylsulfanylmethyl-4-methylpentanoic acid;(S)-2-acetylsulfanyl-methyl-4-methylpentanoic acid; and(R)-2-(2-benzyloxycarbamoyl-3-phenypropionyl-amino)succinic acid1-methyl ester.

Compound (1) Esterification of the Benzoimidazole Carboxylic Acid

An acidic solution (e.g., HCl:water, 30:70) is added to compound (1a)dissolved in a solvent such as methanol. The mixture is refluxed untilcompletion (˜12-36 hours), then concentrated under reduced pressure orin vacuo to afford compound (1b) as a solid. The recovered material maybe used without further processing. Alternately, the solid may bedissolved in ethyl acetate, washed with saturated NaHCO₃, dried overMgSO₄ and concentrated. Acidic solutions used include sulfuric acid anda hydrogen chloride solution (30:70, HCl:H₂O). Examples of compound (1a)include 7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid(R²=methyl, R³=propyl), which is commercially available, and isparticularly well-suited for use in preparing compounds of theinvention. If desired, different R² and R³ groups can be introduced inlater steps. Examples of compound (1b) include7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid methyl ester.

Conversion of the Benzoimidazole Ester to an Alcohol

LiAlH₄ in a solvent such as THF is cooled to 0° C. and stirred undernitrogen. A solution of compound (1b) in the same solvent is addeddropwise and the mixture is stirred at 0° C. After 1 hour, the mixtureis warmed to room temperature and stirred until completion (˜12 hours).The mixture is then cooled to 0° C. Ethyl acetate is added to quench anyremaining LiAlH₄. The reaction is then quenched with saturated NH₄Cl.The mixture is washed with ethyl acetate and the layers separated. Theorganic layer is then dried over MgSO₄ and concentrated. The recoveredsolid is flash chromatographed to produce compound (1c). Examples ofcompound (1c) include (7-methyl-2-propyl-3H-benzoimidazol-5-yl)methanol.

Preparation of Aryl Compound

Compound (1d) can be prepared using synthetic methods that are reportedin the literature, for example Duncia et al. (1991) J. Org. Chem. 56:2395-400, and references cited therein. Alternatively, the startingmaterial in a protected form (1e) may be commercially available. Using acommercially available non-protected starting material (1d), the R¹group is first protected to form protected intermediate (1e), then theleaving group (L) is added to form compound (1f), for example, by ahalogenation reaction. For example, a bromination reaction of a methylgroup of N-triphenylmethyl-5-[4′-methylbiphenyl-2-yl]tetrazole isdescribed in Chao et al. (2005) J. Chinese Chem. Soc. 52:539-544. Inaddition, when Ar* has a —CN group, it can be subsequently converted tothe desired tetrazolyl group, which may be protected. Conversion of thenitrile group is readily achieved by reaction with a suitable azide suchas sodium azide, trialkyltin azide (particularly tributyltin azide) ortriaryltin azide. Compound (1f) when Ar has one of the remainingformulas is readily synthesized using similar techniques or othermethods as are well known in the art.

Exemplary methods of preparing compound (1f) include the following. Asolution of the starting material (1d) and thionyl chloride are stirredat room temperature. After completion of the reaction, the mixture isconcentrated in vacuo to afford a solid, which is dissolved in a solventsuch as THF and cooled to 0° C. Potassium t-butoxide is then added. Uponcompletion of the reaction, the mixture is partitioned between ethylacetate and water. The organic layer is washed with saturated aqueousNaCl, dried over MgSO₄, filtered, and concentrated to afford compound(1e). Alternately, HCl is added to a solution of the starting material(1d) and a solvent such as methanol. The mixture is heated to reflux andstirred until the reaction is complete (˜48 hours), then cooled andconcentrated. The recovered material is dried in vacuo to obtaincompound (1e). Intermediate (1e), benzoyl peroxide, andN-bromosuccinimide are dissolved in CCl₄ or benzene, and heated toreflux. The mixture is stirred to completion, cooled to roomtemperature, filtered, and concentrated in vacuo. The resulting residueis crystallized from diethyl ether and hexane or flash chromatographedto give compound (1f).

Examples of compound (1d) include: 4′-methylbiphenyl-2-carboxylic acid;2,3-difluoro-4-methyl-benzoic acid; and 2-fluoro-4-methylbenzoic acid.Examples of compound (1 e) includeN-triphenylmethyl-5-[4′-methylbiphenyl-2-yl]tetrazole. Examples ofcompound (1f) include: 4′-bromomethylbiphenyl-2-carboxylic acid t-butylester; 4-bromomethyl-2-fluorobenzoic acid methyl ester;5-(4′-bromomethylbiphenyl-2-yl)-1-trityl-1H-tetrazole;4-bromomethylbenzoic acid methyl ester;4-bromomethyl-2,3-difluoro-benzoic acid methyl ester;4′-formyl-biphenyl-2-sulfonic acid t-butylamide;4′-amino-methylbiphenyl-2-carboxylic acid t-butyl ester; and4′-bromomethyl-3′-fluorobiphenyl-2-carboxylic acid t-butyl ester.

Compound (1f) where R¹ is —SO₂NHR^(1d) may be synthesized as follows:

The starting material, 2-bromobenzene-1-sulfonamide, is commerciallyavailable. Reaction of 2-bromobenzene-1-sulfonamide in a solvent such asDMF, with 1,1-dimethoxy-N,N-dimethylmethanamine, followed by theaddition of sodium hydrogen sulfate in water, yields2-bromo-N-[1-dimethylaminometh-(E)-ylidene]benzenesulfonamide. Thiscompound is reacted with 4-methylphenylboronic acid to yield4′-methylbiphenyl-2-sulfonic acid 1-dimethylaminometh-(E)-ylideneamide,then the —(CH₂)_(r)-L¹ moiety is added, for example, by a halogenationreaction, to form compound (1f).

Compound (1f) where the Ar mioiety is substituted may be synthesized asfollows:

The starting material, 2-bromobenzoic acid, is commercially available.Reaction of 2-bromobenzoic acid in a suitable solvent, with t-butylalcohol, DCC and DMAP, yields 2-bromo-benzoic acid t-butyl ester. Thiscompound is reacted with 3-fluoro-4-methylphenyl-boronic acid to yield3′-fluoro-4′-methylbiphenyl-2-carboxylic acid t-butyl ester. The—(CH₂)_(r)-L¹ moiety is then added to form compound (1f), for example,by a halogenation reaction.

Alkylation Procedure

Compound (1g) is formed by the following alkylation reaction. A solutionof compound (1b) in a solvent such as DMF is cooled in an ice bath.Sodium hydride (60 wt % in mineral oil) is added, followed by theaddition of compound (1f). The mixture is gradually warmed to roomtemperature, then stirred until completion (up to 12 hours). The mixtureis then cooled and concentrated in vacuo, and the resultant residuepartitioned between saturated aqueous NaCl or LiCl and ethyl acetate.The organic layer is collected, dried over MgSO₄ and evaporated todryness, yielding compound (1g).

Hydrolysis Procedure (Carboxylic Acid-Terminal A Group)

Compound (1g′) and a solvent such as THF are combined with 1 M NaOH inwater, and the mixture is stirred at room temperature until completion(˜12 hours). The mixture is then acidified to a pH of 4, for examplewith 1M HCl. The solution is extracted with ethyl acetate, andconcentrated under reduced pressure to afford compound (1). Examples ofcompound (1g′) include3-(2′-t-butoxycarbonylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid methyl ester.

Alcohol to Amine Conversion (Amine-Terminal A Group)

Compound (1g″) is combined with a solvent such as DCM, a base such asDIPEA, and 4-dimethylaminopyridine. Methanesulfonyl chloride is added at0° C., and the mixture is warmed to room temperature. After the reactionis complete (˜3 hours), the mixture is concentrated and the materialredissolved in solvent. Sodium azide is added and the mixture is heatedat 80° C. for 1 hour, then cooled to room temperature. The solution ispartitioned between ethyl acetate and 10% LiCl (aqueous). The organiclayer is concentrated and flash chromatographed. The product isdissolved in a solvent such as THF. Triphenylphosphine is added and themixture is stirred at room temperature for 30 minutes. Water is addedand the mixture heated to 60° C. After the reaction is complete (˜3hours), the mixture is cooled to room temperature and concentrated invacuo. The concentrate is dissolved in ethyl acetate, and washed in 1NHCl. The aqueous layer is extracted with ethyl acetate then basified topH˜10, for example with 6N NaOH. The solution is saturated with NaCl,extracted with a solvent such as DCM, and dried over MgSO₄. The organiclayer is then concentrated to afford compound (1). Examples of compound(1g′″) include2-fluoro-4-(6-hydroxymethyl-4-methyl-2-propyl-benzoimidazol-1-ylmethyl)benzoicacid methyl ester.

Compound (2)

Compound (2) can be readily synthesized by following techniquesdescribed in the literature, for example, Neustadt et al (1994) J. Med.Chem. 37:2461-2476 and Moree et al. (1995) J. Org. Chem. 60: 5157-69, aswell as by using the exemplary procedures described below. Examples ofcompound (2), depicted without chirality, include:

Since compound (2) has a chiral center, it may be desirable tosynthesize a particular stereoisomer, and examples are provided asfollows.

Preparation of Chiral Amino Hydroxamate Compound (2^(i))

A base such as DIPEA and a coupling agent such as EDC are added to asolution of compound (2a) in DMF containing HOBt and hydroxylaminehydrochloride. The mixture is stirred at room temperature untilcompletion (˜12 hours), then concentrated in vacuo. The resultingmaterial is distributed between 5% THF in ethyl acetate and IMphosphoric acid. The organic layer is collected and washed with a basesuch as 1M NaOH. The alkaline aqueous layer is then acidified, forexample with 1M phosphoric acid, and extracted with ethyl acetate. Theorganic layer is evaporated and the residue purified by silica gelchromatography to afford compound (2^(i)). Examples of compound (2a)include (R)-3-t-butoxycarbonylamino-4-phenylbutyric acid.

Preparation of Chiral Amino Sulfhydryl Dimer Compound (2^(ii))

Diisopropyl azodicarboxylate is added to a solution oftriphenylphosphine in a solvent such as THF, cooled in an ice bath. Thesolution is stirred and compound (2b) and thioacetic acid are added. Themixture is stirred at 0° C. for 1 hour, then stirred at room temperatureuntil completion (˜12 hours). The mixture is stripped, diluted withethyl acetate, and washed with a cold saturated NaHCO₃ solution. Theorganic layer is dried over MgSO₄, and the filtrate evaporated todryness. The resulting material is flash chromatographed to providecompound (2c). Compound (2c) is dissolved in solvent, followed by theaddition of a base such as 1M LiOH. Air is bubbled through the solutionfor 1 hour followed by the addition of solvent. The mixture is stirredat room temperature until completion (˜24 hours). The solution is thenacidified to pH˜5, for example with acetic acid. The precipitate isfiltered and rinsed with deionized water, producing the compound (2d)dimer. The solid is suspended in MeCN, then concentrated under reducedpressure. The recovered material is dissolved in 4M HCl in 1,4-dioxaneand stirred at room temperature until the reaction is complete (˜2hours). The mixture is then concentrated under reduced pressure, andtriturated with ethyl acetate. The product is filtered, washed withethyl acetate, and dried in vacuo to provide compound (2^(ii)). Examplesof compound (2b) include ((R)-1-benzyl-2-hydroxyethyl)carbamic acidt-butyl ester.

Preparation of Chiral Sulfanyl Acid Compound (2^(iii))

Compound (2e) is formed by dissolving a compound such as D-leucine (forR⁶=isobutyl, for example) in 3M HBr (aqueous) and cooled to 0° C. Asolution of sodium nitrite in water is added, and the mixture stirred at0° C. until completion (˜2.5 hours). The mixture is then extracted withethyl acetate, washed with saturated aqueous NaCl, dried over MgSO₄,filtered, and concentrated to afford compound (2e). Compound (2e) iscombined with potassium thioacetate or sodium thioacetate and DMF, andthe mixture stirred at room temperature until completion (˜1 hour).Water is added. The mixture is then extracted with ethyl acetate, washedwith saturated aqueous NaCl, dried over MgSO₄, filtered, andconcentrated to provide compound (2^(iii)). The product is purified bysilica gel chromatography. Examples of compound (2e) include(R)-2-bromo-4-methylpentanoic acid. Examples of compound (2^(iii))include (S)-2-acetylsulfanyl-4-methylpentanoic acid.

Preparation of Sulfanyl Acid Compound (2^(iv))

Compound (2f) is mixed with diethylamine and cooled in an ice bath. Anaqueous formaldehyde solution (37%) is then added, and the mixturestirred at 0° C. for approximately 2 hours, warmed to room temperatureand stirred overnight. The mixture is then extracted with ether, washed,dried, and evaporated to dryness, to provide compound (2g). Compound(2g) is then dissolved in 1,4-dioxane, and a 1M NaOH solution is added.The mixture is stirred at room temperature until completion(approximately 2 days). The organic solvent is removed in vacuo, and theaqueous residue is rinsed with EtOAc and acidified to approximately pH 1with concentrated HCl. The product is extracted with EtOAc, dried, andevaporated to dryness to yield compound (2h). Compound (2h) is combinedwith thiolacetic acid (10 mL), and the mixture is stirred at 80° C.until completion (approximately 2 hours), then concentrated to drynessto yield compound (2^(iv)) which is dissolved in toluene andconcentrated to remove any trace of thiolacetic acid. Examples ofcompound (2f) include 2-benzylmalonic acid monoethyl ester (R⁶=benzyl)and 2-isobutylmalonic acid monoethyl ester (R⁶=isobutyl).

Preparation of Chiral Sulfanyl Acid Compound (2^(v))

Compound (2i), (S)-4-benzyl-2-oxazolidinone, is commercially available.Compound (2j) is also typically commercially available or can be readilysynthesized. For example, R⁶—CH₂—COOH (for example, isocaproic acid or3-phenylpropionic acid) is dissolved in methylene chloride and thionylchloride is added. The mixture is stirred at room temperature until thereaction is complete (for example, overnight), and then concentrated toprovide (2j). Examples of compound (2j) include 4-methylpentanoylchloride and 3-phenylpropionyl chloride.

Compound (2i) is dissolved in a suitable solvent and cooled (−78° C.)under nitrogen. n-Butyllithium in hexanes is added dropwise and stirred,followed by the addition of (2j) dropwise. The mixture is stirred at−78° C., then warmed to 0° C. Saturated NaHCO₃ is added and the mixturewarmed to room temperature. The mixture is extracted, washed, dried,filtered, and concentrated to afford (2k). Compound (2k) is dissolved inDCM and stirred at 0° C. under nitrogen. 1M Titanium tetrachloride isadded, followed by 1,3,5-trioxane, all in appropriate solvents. A secondequivalent of 1M titanium tetrachloride is added and the mixture stirredat 0° C. until the reaction is complete. The reaction is then quenchedwith saturated ammonium chloride. Appropriate solvents are added, theaqueous phase is extracted, and the organic layers are combined, dried,filtered, and concentrated to provide (2l), which can then be purifiedby silica gel chromatography or used in the next step without furtherpurification. Compound (2l) is dissolved in a solvent, to which is added9 M hydrogen peroxide in water, followed by the dropwise addition of 1.5M lithium hydroxide monohydrate in water. The mixture is warmed to roomtemperature and stirred. Optionally, potassium hydroxide may be addedand the mixture heated at 60° C. then cooled at room temperature. Tothis is added an aqueous solution of sodium sulfite followed by waterand chloroform. The aqueous layer is extracted, acidified and extractedagain. The organic layer is washed, dried, filtered, and rotovaped toprovide (2m). Triphenylphosphine is dissolved in an appropriate solventand cooled at 0° C. (ice bath). Diisopropyl azodicarboxylate is addeddropwise and the mixture stirred. Compound (2m) and thioacetic acid,dissolved in an appropriate solvent, are added dropwise to the mixture.After the addition, the mixture is removed from the ice bath and stirredat room temperature until the reaction is complete (approximately 3.5hours), concentrated, and then partitioned. The organic layer isextracted and the combined aqueous extracts washed, acidified andextracted. The organic layer is washed again, dried, filtered, androtovaped to provide compound (2^(v)). Examples of compound (2^(v))include (S)-2-acetylsulfanylmethyl-4-methylpentanoic acid.

Scheme II Peptide Coupling Reaction

Compounds of formula I can also be prepared by coupling compound (3) andcompound (1) where A is —COOH, followed by reaction with compound (4).In compounds (1) and (3), the sum of a and b is in the range of 0 to 11.In compounds (3) and (4), the [R⁵] and [[R⁵]] moieties representportions of the R⁵ moiety. For example, if R⁵ is —CH₂C(O)N(OH)H, then[R⁵] would be —CH₂C(O)— and [[R⁵]] would be —N(OH)H.

The amide coupling of compounds (1) and (3) is typically conducted atroom temperature with coupling reagents such as pentafluorophenolcombined with EDC and DIPEA in solvents such as DMF. Compounds (3) and(4) are available commercially or can be readily synthesized bytechniques that are well known in the art. Examples of compound (3)include 3-amino-4-(3-chlorophenyl)butyric acid. Examples of compound (4)include H₂NOH, H₂NO-benzyl, and H₂NO-t-butyl.

Scheme III Peptide Coupling Reaction

Compounds of formula I can also be prepared by coupling compounds (1)and (5) under conventional amide bond-forming conditions. This synthesisis particularly useful for preparing compounds of formula I where morethan one —CH₂— moiety in the alkylene is replaced with —NR^(4a)—C(O) or—C(O)—NR^(4a). In the compounds depicted below, b will typically be atleast 1 and the sum of a, b and c is in the range of 1 to 10.

Compound (5) is formed by converting the ester compound (6) to the acidwith a base, converting the acid to the dioxopyrrolidinyl ester withN-hydroxysuccinimide, then converting the dioxopyrrolidinyl ester withcompound (7) to form compound (5). Compound (5) may have one or moreR^(4b) substituents on the carbon atoms in the —(CH₂)_(b)— and/or—(CH₂)_(c)— portions.

Compound (6) can be readily synthesized by following the techniquesdescribed in the literature, for example, Fournie-Zaluski et al. (1985)J. Med. Chem. 28(9):1158-1169). Examples of compound (6) include2-benzyl-N-benzyloxymalonamic acid ethyl ester. Compound (7) isavailable commercially or can be readily synthesized by techniques thatare well known in the art. This reactant is particularly useful where acarbon atom in the alkylene moiety in X is substituted with an R^(4b)group. For example, 2-aminosuccinic acid 1-methyl ester is an example ofcompound (7) that is useful for preparing compounds where R^(4b) is—COOH, where the R^(4b) moiety is in a protected form, —C(O)OCH₃.

Compounds of formula I can also be prepared by a two-step method, wherethe first step involves the addition of a halogen-substituted alkanoicacid (“L-acid”) such as α-bromoisocaproic acid to compound (1), toprovide Intermediate (8), where L is a leaving group such as bromo.Intermediate (8) is then reacted with a thiol or sulfur-containingnucleophilic reactant that contains the desired R⁵ group, for example,potassium thioacetate or thiourea.

Scheme V Prodrug Synthesis

Prodrugs can be readily synthesized using the techniques describedabove. In addition, prodrugs can be formed by further modifying activecompounds of formula I where Ar**—COOH represents Ar—R¹ and R⁵ is—C₀₋₃alkylene-SH, as shown below:

Thus, both prodrug A and prodrug C can be readily synthesized from thecorresponding active compound.

If desired, pharmaceutically acceptable salts of the compounds offormula I can be prepared by contacting the free acid or base form of acompound of formula I with a pharmaceutically acceptable base or acid.

Certain intermediates described herein are believed to be novel andaccordingly, such compounds are provided as further aspects of theinvention including, for example, the compounds of formulas II, III andIV, and salts thereof:

wHere Ar* is Ar—R¹*; Ar, r, n, and R²⁻³, X, and R⁵⁻⁷ are as defined forformula I; and R¹* is —C(O)O—P², —SO₂O—P⁵, —SO₂NH—P⁶, —P(O)(O—P⁷)₂,—OCH(CH₃)—C(O)O—P², —OCH(aryl)-C(O)O—P², or tetrazol-5-yl-P⁴; where P²is a carboxy-protecting group, P⁴ is a tetrazole-protecting group, P⁵ isa hydroxyl-protecting group, P⁶ is a sulfonamide-protecting group, andP⁷ is a phosphate-protecting group or phosphinate-protecting group;

where Ar, r, n, R²⁻³, X, and R⁶⁻⁷ are as defined for formula I; R⁵* isselected from —C₀₋₃alkylene-S—P³, —C₀₋₃alkylene-C(O)NH(O—P⁵),—C₀₋₃alkylene-N(O—P⁵)—C(O)R^(5d), —C₀₋₁alkylene-NHC(O)CH₂S—P³,—NH—C₀₋₁alkylene-P(O)(O—P⁷)₂, —C₀₋₃alkylene-P(O)(O—P⁷)—R^(5f),—C₀₋₂alkylene-CHR^(5g)C(O)O—P² and—C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—C(O)O—P²; and R^(5d-i) are as definedfor formula I; where P² is a carboxy-protecting group, P³ is athiol-protecting group, P⁵ is a hydroxyl-protecting group, and P⁷ is aphosphate-protecting group or phosphinate-protecting group; and

where Ar* is Ar—R¹*; Ar, r, n, R²⁻³, X, and R⁶⁻⁷ are as defined forformula I; R¹* is —C(O)O—P², —SO₂O—P⁵, —SO₂NH—P⁶, —P(O)(O—P⁷)₂,—OCH(CH₃)—C(O)O—P², —OCH(aryl)-C(O)O—P², or tetrazol-5-yl-P⁴; R⁵* is—C₀₋₃alkylene-S—P³, —C₀₋₃alkylene-C(O)NH(O—P⁵),—C₀₋₃alkylene-N(O—P⁵)—C(O)R^(1d), —C₀ lalkylene-NHC(O)CH₂S—P³,—NH—C₀₋₁alkylene-P(O)(O—P⁷)₂, —C₀₋₃alkylene-P(O)(O—P⁷)—R^(5f),—C₀₋₂alkylene-CHR^(5g)—C(O)O—P², or—C₀₋₃alkylene-C(O)NR^(5h)—CHR^(5i)—C(O)O—P²; and R^(5d-i) are as definedfor formula I; where P² is a carboxy-protecting group, P³ is athiol-protecting group, P⁴ is a tetrazole-protecting group, P⁵ is ahydroxyl-protecting group, P⁶ is a sulfonamide-protecting group, and P⁷is a phosphate-protecting group or phosphinate-protecting group. Thus,another method of preparing compounds of the invention involvesdeprotecting a compound of formula II, III, or IV.

In one embodiment, r and n are both 1, and the intermediates arecompounds of formulas IIa, IIIa and IVa, and salts thereof:

where Ar*, Ar, R²⁻³, X, R⁵*, R⁵⁻⁷ are as defined above.

Further details regarding specific reaction conditions and otherprocedures for preparing representative compounds of the invention orintermediates thereof are described in the Examples set forth below.

Utility

Compounds of the invention possess angiotensin II type 1 (AT₁) receptorantagonist activity. In one embodiment, compounds of the invention areselective for inhibition of the AT₁ receptor over the AT₂ receptor.Compounds of the invention also possess neprilysin (NEP) inhibitionactivity, that is, the compounds are able to inhibit enzyme-substrateactivity. In another embodiment, the compounds do not exhibitsignificant inhibitory activity at the angiotensin-converting enzyme.Compounds of formula I may be active drugs as well as prodrugs. Thus,when discussing the activity of compounds of the invention, it isunderstood that any such prodrugs have the expected activity oncemetabolized.

One measure of the affinity of a compound for the AT₁ receptor is theinhibitory constant (K_(i)) for binding to the AT₁ receptor. The pK_(i)value is the negative logarithm to base 10 of the K_(i). One measure ofthe ability of a compound to inhibit NEP activity is the inhibitoryconcentration (IC₅₀), which is the concentration of compound thatresults in half-maximal inhibition of substrate conversion by the NEPenzyme. The pIC₅₀ value is the negative logarithm to base 10 of theIC₅₀. Compounds of formula I and pharmaceutically acceptable saltsthereof that have both AT₁ receptor-antagonizing activity and NEPenzyme-inhibiting activity are of particular interest, including thosethat exhibit a pK_(i) at the AT₁ receptor greater than or equal to about5.0, and exhibit a pIC₅₀ for NEP greater than or equal to about 5.0.

In one embodiment, compounds of interest have a pK_(i) at the AT₁receptor ≧about 6.0, a pK_(i) at the AT₁ receptor ≧about 7.0, or apK_(i) at the AT₁ receptor ≧about 8.0. Compounds of interest alsoinclude those having a pIC₅₀ for NEP ≧about 6.0 or a pIC₅₀ for NEP≧about 7.0. In another embodiment, compounds of interest have a pK_(i)at the AT₁ receptor within the range of about 8.0-10.0 and a pIC₅₀ forNEP within the range of about 7.0-10.0.

In another embodiment, compounds of particular interest have a pK_(i)for binding to an AT₁ receptor greater than or equal to about 7.5 and aNEP enzyme pIC₅₀ greater than or equal to about 7.0. In anotherembodiment, compounds of interest have a pK_(i) greater than or equal toabout 8.0 and a pIC₅₀ greater than or equal to about 8.0.

It is noted that in some cases, compounds of the invention, while stillhaving dual activity, may possess either weak AT₁ receptor antagonistactivity or weak NEP inhibition activity. In such cases, those of skillin the art will recognize that these compounds still have utility asprimarily either a NEP inhibitor or an AT₁ receptor antagonist,respectively, or have utility as research tools.

Exemplary assays to determine properties of compounds of the invention,such as the AT₁ receptor binding and/or NEP inhibiting activity, aredescribed in the Examples and include by way of illustration and notlimitation, assays that measure AT₁ and AT₂ binding (described in Assay1), and NEP inhibition (described in Assay 2). Useful secondary assaysinclude assays to measure ACE inhibition (also described in Assay 2) andaminopeptidase P (APP) inhibition (described in Sulpizio et al. (2005)JPET 315:1306-1313). A pharmacodynamic assay to assess the in vivoinhibitory potencies for ACE, AT₁, and NEP in anesthetized rats isdescribed in Assay 3 (see also Seymour et al. Hypertension 7(SupplI):I-35-1-42, 1985 and Wigle et al. Can. J. Physiol. Pharmacol.70:1525-1528, 1992), where AT₁ inhibition is measured as the percentinhibition of the angiotensin II pressor response, ACE inhibition ismeasured as the percent inhibition of the angiotensin I pressorresponse, and NEP inhibition is measured as increased urinary cyclicguanosine 3′, 5′-monophosphate (cGMP) output. Useful in vivo assaysinclude the conscious spontaneously hypertensive rat (SHR) model, whichis a renin dependent hypertension model useful for measuring AT₁receptor blocking (described in Assay 4; see also Intengan et al. (1999)Circulation 100(22):2267-2275 and Badyal et al. (2003) Indian Journal ofPharmacology 35:349-362), and the conscious desoxycorticosteroneacetate-salt (DOCA-salt) rat model, which is a volume dependenthypertension model useful for measuring NEP activity (described in Assay5; see also Trapani et al. (1989) J. Cardiovasc. Pharmacol. 14:419-424,Intengan et al. (1999) Hypertension 34(4):907-913, and Badyal et al.(2003) supra). Both the SHR and DOCA-salt models are useful forevaluating the ability of a test compound to reduce blood pressure. TheDOCA-salt model is also useful to measure a test compound's ability toprevent or delay a rise in blood pressure. Compounds of the inventionare expected to antagonize the AT₁ receptor and/or inhibit the NEPenzyme in any of the assays listed above, or assays of a similar nature.Thus, the aforementioned assays are useful in determining thetherapeutic utility of compounds of the invention, for example, theirutility as antihypertensive agents. Other properties and utilities ofcompounds of the invention can be demonstrated using other in vitro andin vivo assays well-known to those skilled in the art.

Compounds of the invention are expected to be useful for the treatmentand/or prevention of medical conditions responsive to AT₁ receptorantagonism and/or NEP inhibition. Thus it is expected that patientssuffering from a disease or disorder that is treated by antagonizing theAT₁ receptor and/or by inhibiting the NEP enzyme can be treated byadministering a therapeutically effective amount of a compound of theinvention. For example, by antagonizing the AT₁ receptor and thusinterfering with the action of angiotensin II on its receptors, thesecompounds are expected to find utility in preventing the increase inblood pressure produced by angiotensin II, a potent vasopressor. Inaddition, by inhibiting NEP, the compounds are also expected topotentiate the biological effects of endogenous peptides that aremetabolized by NEP, such as the natriuretic peptides, bombesin,bradykinins, calcitonin, endothelins, enkephalins, neurotensin,substance P and vasoactive intestinal peptide. For example, bypotentiating the effects of the natriuretic peptides, compounds of theinvention are expected to be useful to treat glaucoma. The compounds arealso expected to have other physiological actions, for example, on therenal, central nervous, reproductive and gastrointestinal systems.

Compounds of the invention are expected to find utility in treatingand/or preventing medical conditions such as cardiovascular and renaldiseases. Cardiovascular diseases of particular interest include heartfailure such as congestive heart failure, acute heart failure, chronicheart failure, and acute and chronic decompensated heart failure. Renaldiseases of particular interest include diabetic nephropathy and chronickidney disease. One embodiment of the invention is directed to a methodfor treating hypertension, comprising administering to a patient atherapeutically effective amount of a compound of the invention.Typically, the therapeutically effective amount is the amount that issufficient to lower the patient's blood pressure. In one embodiment, thecompound is administered as an oral dosage form.

Another embodiment of the invention is directed to a method for treatingheart failure, comprising administering to a patient a therapeuticallyeffective amount of a compound of the invention. Typically, thetherapeutically effective amount is the amount that is sufficient tolower blood pressure and/or improve renal functions. In one embodiment,the compound is administered as an intravenous dosage form. When used totreat heart failure, the compound may be administered in combinationwith other therapeutic agents such as diuretics, natriuretic peptides,and adenosine receptor antagonists.

Compounds of the invention are also expected to be useful inpreventative therapy, for example in preventing the progression ofcardiac insufficiency after myocardial infarction, preventing arterialrestenosis after angioplasty, preventing thickening of blood vesselwalls after vascular operations, preventing atherosclerosis, andpreventing diabetic angiopathy.

In addition, as NEP inhibitors, compounds of the invention are expectedto inhibit enkephalinase, which will inhibit the degradation ofendogenous enkephalins. Thus, such compounds may also find utility asanalgesics. Due to their NEP inhibition properties, compounds of theinvention are also expected to be useful as antitussive agents andantidiarrheal agents (for example, for the treatment of waterydiarrhea), as well as find utility in the treatment of menstrualdisorders, preterm labor, pre-eclampsia, endometriosis, reproductivedisorders (for example, male and female infertility, polycystic ovariansyndrome, implantation failure), and male and female sexual dysfunction,including male erectile dysfunction and female sexual arousal disorder.More specifically, the compounds of the invention are expected to beuseful in treating female sexual dysfunction, which is often defined asa female patient's difficulty or inability to find satisfaction insexual expression. This covers a variety of diverse female sexualdisorders including, by way of illustration and not limitation,hypoactive sexual desire disorder, sexual arousal disorder, orgasmicdisorder and sexual pain disorders. When used to treat such disorders,especially female sexual dysfunction, compounds of the invention may becombined with one or more of the following secondary agents: PDE5inhibitors, dopamine agonists, estrogen receptor agonists and/orantagonists, androgens, and estrogens.

The amount of the compound of the invention administered per dose or thetotal amount administered per day may be predetermined or it may bedetermined on an individual patient basis by taking into considerationnumerous factors, including the nature and severity of the patient'scondition, the condition being treated, the age, weight, and generalhealth of the patient, the tolerance of the patient to the active agent,the route of administration, pharmacological considerations such as theactivity, efficacy, pharmacokinetics and toxicology profiles of thecompound and any secondary agents being administered, and the like.Treatment of a patient suffering from a disease or medical condition(such as hypertension) can begin with a predetermined dosage or a dosagedetermined by the treating physician, and will continue for a period oftime necessary to prevent, ameliorate, suppress, or alleviate thesymptoms of the disease or medical condition. Patients undergoing suchtreatment will typically be monitored on a routine basis to determinethe effectiveness of therapy. For example, in treating hypertension,blood pressure measurements may be used to determine the effectivenessof treatment. Similar indicators for other diseases and conditionsdescribed herein, are well-known and are readily available to thetreating physician. Continuous monitoring by the physician will insurethat the optimal amount of the compound of the invention will beadministered at any given time, as well as facilitating thedetermination of the duration of treatment. This is of particular valuewhen secondary agents are also being administered, as their selection,dosage, and duration of therapy may also require adjustment. In thisway, the treatment regimen and dosing schedule can be adjusted over thecourse of therapy so that the lowest amount of active agent thatexhibits the desired effectiveness is administered and, further, thatadministration is continued only so long as is necessary to successfullytreat the disease or medical condition.

Since compounds of the invention possess AT₁ receptor antagonistactivity and/or NEP enzyme inhibition activity, such compounds are alsouseful as research tools for investigating or studying biologicalsystems or samples having AT₁ receptors or a NEP enzyme, for example tostudy diseases where the AT₁ receptor or NEP enzyme plays a role. Anysuitable biological system or sample having AT₁ receptors and/or a NEPenzyme may be employed in such studies which may be conducted either invitro or in vivo. Representative biological systems or samples suitablefor such studies include, but are not limited to, cells, cellularextracts, plasma membranes, tissue samples, isolated organs, mammals(such as mice, rats, guinea pigs, rabbits, dogs, pigs, humans, and soforth), and the like, with mammals being of particular interest. In oneparticular embodiment of the invention an AT₁ receptor in a mammal isantagonized by administering an AT₁-antagonizing amount of a compound ofthe invention. In another particular embodiment, NEP enzyme activity ina mammal is inhibited by administering a NEP-inhibiting amount of acompound of the invention. Compounds of the invention can also be usedas research tools by conducting biological assays using such compounds.

When used as a research tool, a biological system or sample comprisingan AT₁ receptor and/or a NEP enzyme is typically contacted with an AT₁receptor-antagonizing or NEP enzyme-inhibiting amount of a compound ofthe invention. After the biological system or sample is exposed to thecompound, the effects of antagonizing the AT₁ receptor and/or inhibitingthe NEP enzyme are determined using conventional procedures andequipment, such as by measuring receptor binding in a binding assay ormeasuring ligand-mediated changes in a functional assay. Exposureencompasses contacting cells or tissue with the compound, administeringthe compound to a mammal, for example by ip., i.v. or s.c.administration, and so forth. This determining step can involvemeasuring a response, i.e., a quantitative analysis or may comprise anobservation, i.e., a qualitative analysis. Measuring a responseinvolves, for example, determining the effects of the compound on thebiological system or sample using conventional procedures and equipment,such as radioligand binding assays and measuring ligand-mediated changesin functional assays. The assay results can be used to determine theactivity level as well as the amount of compound necessary to achievethe desired result, i.e., an AT₁ receptor-antagonizing and/or a NEPenzyme-inhibiting amount. Typically, the determining step will involvedetermining the AT₁ receptor ligand-mediated effects and/or determiningthe effects of inhibiting the NEP enzyme.

Additionally, compounds of the invention can be used as research toolsfor evaluating other chemical compounds, and thus are also useful inscreening assays to discover, for example, new compounds having AT₁receptor-antagonizing activity and/or NEP-inhibiting activity. In thismanner, a compound of the invention is used as a standard in an assay toallow comparison of the results obtained with a test compound and withcompounds of the invention to identify those test compounds that haveabout equal or superior activity, if any. For example, K_(i) data (asdetermined, for example, by a binding assay) for a test compound or agroup of test compounds is compared to the K_(i) data for a compound ofthe invention to identify those test compounds that have the desiredproperties, for example, test compounds having a K_(i) value about equalor superior to a compound of the invention, if any. This aspect of theinvention includes, as separate embodiments, both the generation ofcomparison data (using the appropriate assays) and the analysis of testdata to identify test compounds of interest. Thus, a test compound canbe evaluated in a biological assay, by a method comprising the steps of:(a) conducting a biological assay with a test compound to provide afirst assay value; (b) conducting the biological assay with a compoundof the invention to provide a second assay value; wherein step (a) isconducted either before, after or concurrently with step (b); and (c)comparing the first assay value from step (a) with the second assayvalue from step (b). Exemplary biological assays include an AT₁ receptorbinding assay and a NEP enzyme inhibition assay.

Pharmaceutical Compositions and Formulations

Compounds of the invention are typically administered to a patient inthe form of a pharmaceutical composition or formulation. Suchpharmaceutical compositions may be administered to the patient by anyacceptable route of administration including, but not limited to, oral,rectal, vaginal, nasal, inhaled, topical (including transdermal),ocular, and parenteral modes of administration. Further, the compoundsof the invention may be administered, for example orally, in multipledoses per day (for example, two, three, or four times daily), in asingle daily dose or a single weekly dose. It will be understood thatany form of the compounds of the invention, (i.e., free base, free acid,pharmaceutically acceptable salt, solvate, etc.) that is suitable forthe particular mode of administration can be used in the pharmaceuticalcompositions discussed herein.

Accordingly, in one embodiment, the invention is directed to apharmaceutical composition comprising a pharmaceutically acceptablecarrier and a compound of the invention. The compositions may containother therapeutic and/or formulating agents if desired. When discussingcompositions, the “compound of the invention” may also be referred toherein as the “active agent,” to distinguish it from other components ofthe formulation, such as the carrier. Thus, it is understood that theterm “active agent” includes compounds of formula I as well aspharmaceutically acceptable salts, solvates and prodrugs of thatcompound.

The pharmaceutical compositions of the invention typically contain atherapeutically effective amount of a compound of the invention. Thoseskilled in the art will recognize, however, that a pharmaceuticalcomposition may contain more than a therapeutically effective amount,such as in bulk compositions, or less than a therapeutically effectiveamount, such as in individual unit doses designed for multipleadministration to achieve a therapeutically effective amount. Typically,the composition will contain from about 0.01-95 wt % of active agent,including, from about 0.01-30 wt %, such as from about 0.01-10 wt %,with the actual amount depending upon the formulation itself, the routeof administration, the frequency of dosing, and so forth. In oneembodiment, a composition suitable for an oral dosage form, for example,may contain about 5-70 wt %, or from about 10-60 wt % of active agent.

Any conventional carrier or excipient may be used in the pharmaceuticalcompositions of the invention. The choice of a particular carrier orexcipient, or combinations of carriers or excipients, will depend on themode of administration being used to treat a particular patient or typeof medical condition or disease state. In this regard, the preparationof a suitable composition for a particular mode of administration iswell within the scope of those skilled in the pharmaceutical arts.Additionally, carriers or excipients used in such compositions arecommercially available. By way of further illustration, conventionalformulation techniques are described in Remington: The Science andPractice of Pharmacy, 20^(th) Edition, Lippincott Williams & White,Baltimore, Md. (2000); and H. C. Ansel et al., Pharmaceutical DosageForms and Drug Delivery Systems, 7^(th) Edition, Lippincott Williams &White, Baltimore, Md. (1999).

Representative examples of materials which can serve as pharmaceuticallyacceptable carriers include, but are not limited to, the following:sugars, such as lactose, glucose and sucrose; starches, such as cornstarch and potato starch; cellulose, such as microcrystalline cellulose,and its derivatives, such as sodium carboxymethyl cellulose, ethylcellulose and cellulose acetate; powdered tragacanth; malt; gelatin;talc; excipients, such as cocoa butter and suppository waxes; oils, suchas peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil,corn oil and soybean oil; glycols, such as propylene glycol; polyols,such as glycerin, sorbitol, mannitol and polyethylene glycol; esters,such as ethyl oleate and ethyl laurate; agar; buffering agents, such asmagnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-freewater; isotonic saline; Ringer's solution; ethyl alcohol; phosphatebuffer solutions; compressed propellant gases, such aschlorofluorocarbons and hydrofluorocarbons; and other non-toxiccompatible substances employed in pharmaceutical compositions.

Pharmaceutical compositions are typically prepared by thoroughly andintimately mixing or blending the active agent with a pharmaceuticallyacceptable carrier and one or more optional ingredients. The resultinguniformly blended mixture may then be shaped or loaded into tablets,capsules, pills, canisters, cartridges, dispensers and the like usingconventional procedures and equipment.

In those formulations where the compound of the invention contains athiol group, additional consideration may be given to minimize oreliminate oxidation of the thiol to form a disulfide. In solidformulations, this may be accomplished by reducing the drying time,decreasing the moisture content of the formulation, and includingmaterials such as ascorbic acid, sodium ascorbate, sodium sulfite andsodium bisulfite, as well as materials such as a mixture of lactose andmicrocrystalline cellulose. In liquid formulations, stability of thethiol may be improved by the addition of amino acids, antioxidants, or acombination of disodium edetate and ascorbic acid.

In one embodiment, the pharmaceutical compositions are suitable for oraladministration. Suitable compositions for oral administration may be inthe form of capsules, tablets, pills, lozenges, cachets, dragees,powders, granules; solutions or suspensions in an aqueous or non-aqueousliquid; oil-in-water or water-in-oil liquid emulsions; elixirs orsyrups; and the like; each containing a predetermined amount of theactive agent.

When intended for oral administration in a solid dosage form (capsules,tablets, pills and the like), the composition will typically comprisethe active agent and one or more pharmaceutically acceptable carriers,such as sodium citrate or dicalcium phosphate. Solid dosage forms mayalso comprise: fillers or extenders, such as starches, microcrystallinecellulose, lactose, sucrose, glucose, mannitol, and/or silicic acid;binders, such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and/or acacia; humectants, such as glycerol;disintegrating agents, such as agar-agar, calcium carbonate, potato ortapioca starch, alginic acid, certain silicates, and/or sodiumcarbonate; solution retarding agents, such as paraffin; absorptionaccelerators, such as quaternary ammonium compounds; wetting agents,such as cetyl alcohol and/or glycerol monostearate; absorbents, such askaolin and/or bentonite clay; lubricants, such as talc, calciumstearate, magnesium stearate, solid polyethylene glycols, sodium laurylsulfate, and/or mixtures thereof; coloring agents; and buffering agents.

Release agents, wetting agents, coating agents, sweetening, flavoringand perfuming agents, preservatives and antioxidants may also be presentin the pharmaceutical compositions. Exemplary coating agents fortablets, capsules, pills and like, include those used for entericcoatings, such as cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate, methacrylicacid-methacrylic acid ester copolymers, cellulose acetate trimellitate,carboxymethyl ethyl cellulose, hydroxypropyl methyl cellulose acetatesuccinate, and the like. Examples of pharmaceutically acceptableantioxidants include: water-soluble antioxidants, such as ascorbic acid,cysteine hydrochloride, sodium bisulfate, sodium metabisulfate sodiumsulfite and the like; oil-soluble antioxidants, such as ascorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene, lecithin,propyl gallate, alpha-tocopherol, and the like; and metal-chelatingagents, such as citric acid, ethylenediamine tetraacetic acid, sorbitol,tartaric acid, phosphoric acid, and the like.

Compositions may also be formulated to provide slow or controlledrelease of the active agent using, by way of example, hydroxypropylmethyl cellulose in varying proportions or other polymer matrices,liposomes and/or microspheres. In addition, the pharmaceuticalcompositions of the invention may contain opacifying agents and may beformulated so that they release the active agent only, orpreferentially, in a certain portion of the gastrointestinal tract,optionally, in a delayed manner. Examples of embedding compositionswhich can be used include polymeric substances and waxes. The activeagent can also be in micro-encapsulated form, if appropriate, with oneor more of the above-described excipients.

Suitable liquid dosage forms for oral administration include, by way ofillustration, pharmaceutically acceptable emulsions, microemulsions,solutions, suspensions, syrups and elixirs. Liquid dosage formstypically comprise the active agent and an inert diluent, such as, forexample, water or other solvents, solubilizing agents and emulsifiers,such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethylacetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyleneglycol, oils (for example, cottonseed, groundnut, corn, germ, olive,castor and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethyleneglycols and fatty acid esters of sorbitan, and mixtures thereof.Suspensions may contain suspending agents such as, for example,ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitanesters, microcrystalline cellulose, aluminium metahydroxide, bentonite,agar-agar and tragacanth, and mixtures thereof.

When intended for oral administration, the pharmaceutical compositionsof the invention may be packaged in a unit dosage form. The term “unitdosage form” refers to a physically discrete unit suitable for dosing apatient, i.e., each unit containing a predetermined quantity of theactive agent calculated to produce the desired therapeutic effect eitheralone or in combination with one or more additional units. For example,such unit dosage forms may be capsules, tablets, pills, and the like.

In another embodiment, the compositions of the invention are suitablefor inhaled administration, and will typically be in the form of anaerosol or a powder. Such compositions are generally administered usingwell-known delivery devices, such as a nebulizer, dry powder, ormetered-dose inhaler. Nebulizer devices produce a stream of highvelocity air that causes the composition to spray as a mist that iscarried into a patient's respiratory tract. An exemplary nebulizerformulation comprises the active agent dissolved in a carrier to form asolution, or micronized and combined with a carrier to form a suspensionof micronized particles of respirable size. Dry powder inhalersadminister the active agent as a free-flowing powder that is dispersedin a patient's air-stream during inspiration. An exemplary dry powderformulation comprises the active agent dry-blended with an excipientsuch as lactose, starch, mannitol, dextrose, polylactic acid,polylactide-co-glycolide, and combinations thereof. Metered-doseinhalers discharge a measured amount of the active agent usingcompressed propellant gas. An exemplary metered-dose formulationcomprises a solution or suspension of the active agent in a liquefiedpropellant, such as a chlorofluorocarbon or hydrofluoroalkane. Optionalcomponents of such formulations include co-solvents, such as ethanol orpentane, and surfactants, such as sorbitan trioleate, oleic acid,lecithin, glycerin, and sodium lauryl sulfate. Such compositions aretypically prepared by adding chilled or pressurized hydrofluoroalkane toa suitable container containing the active agent, ethanol (if present)and the surfactant (if present). To prepare a suspension, the activeagent is micronized and then combined with the propellant.Alternatively, a suspension formulation can be prepared by spray dryinga coating of surfactant on micronized particles of the active agent. Theformulation is then loaded into an aerosol canister, which forms aportion of the inhaler.

Compounds of the invention can also be administered parenterally (e.g.,by subcutaneous, intravenous, intramuscular, or intraperitonealinjection). For such administration, the active agent is provided in asterile solution, suspension, or emulsion. Exemplary solvents forpreparing such formulations include water, saline, low molecular weightalcohols such as propylene glycol, polyethylene glycol, oils, gelatin,fatty acid esters such as ethyl oleate, and the like. Parenteralformulations may also contain one or more anti-oxidants, solubilizers,stabilizers, preservatives, wetting agents, emulsifiers, and dispersingagents. Surfactants, additional stabilizing agents or pH-adjustingagents (acids, bases or buffers) and anti-oxidants are particularlyuseful to provide stability to the formulation, for example, to minimizeor avoid hydrolysis of ester and amide linkages, or dimerization ofthiols that may be present in the compound. These formulations may berendered sterile by use of a sterile injectable medium, a sterilizingagent, filtration, irradiation, or heat. In one particular embodiment,the parenteral formulation comprises an aqueous cyclodextrin solution asthe pharmaceutically acceptable carrier. Suitable cyclodextrins includecyclic molecules containing six or more α-D-glucopyranose units linkedat the 1,4 positions by a linkages as in amylase, β-cyclodextrin orcycloheptaamylose. Exemplary cyclodextrins include cyclodextrinderivatives such as hydroxypropyl and sulfobutyl ether cyclodextrinssuch as hydroxypropyl-β-cyclodextrin and sulfobutyl etherβ-cyclodextrin. Exemplary buffers for such formulations includecarboxylic acid-based buffers such as citrate, lactate and maleatebuffer solutions.

Compounds of the invention can also be administered transdermally usingknown transdermal delivery systems and excipients. For example, thecompound can be admixed with permeation enhancers, such as propyleneglycol, polyethylene glycol monolaurate, azacycloalkan-2-ones and thelike, and incorporated into a patch or similar delivery system.Additional excipients including gelling agents, emulsifiers and buffers,may be used in such transdermal compositions if desired.

If desired, the compounds of the invention may be administered incombination with one or more other therapeutic agents. Thus, in oneembodiment, pharmaceutical compositions of the invention contain otherdrugs that are co-administered with a compound of the invention. Forexample, the composition may further comprise one or more drugs (alsoreferred to as “secondary agents(s)”) selected from the group ofdiuretics, β₁ adrenergic receptor blockers, calcium channel blockers,angiotensin-converting enzyme inhibitors, AT₁ receptor antagonists,neprilysin inhibitors, non-steroidal anti-inflammatory agents,prostaglandins, anti-lipid agents, anti-diabetic agents, anti-thromboticagents, renin inhibitors, endothelin receptor antagonists, endothelinconverting enzyme inhibitors, aldosterone antagonists,angiotensin-converting enzyme/neprilysin inhibitors, and combinationsthereof. Such therapeutic agents are well known in the art, and examplesare described below. By combining a compound of the invention with asecondary agent, triple therapy can be achieved: AT₁ receptor antagonistactivity, NEP inhibition activity and activity associated with thesecondary agent (for example, β₁ adrenergic receptor blocker) can beachieved using only two active components. Since compositions containingtwo active components are typically easier to formulate thancompositions containing three active components, such two-componentcompositions provide a significant advantage over compositionscontaining three active components. Accordingly, in yet another aspectof the invention, a pharmaceutical composition comprises a compound ofthe invention, a second active agent, and a pharmaceutically acceptablecarrier. Third, fourth etc. active agents may also be included in thecomposition. In combination therapy, the amount of compound of theinvention that is administered, as well as the amount of secondaryagents, may be less than the amount typically administered inmonotherapy.

Compounds of the invention may be either physically mixed with thesecond active agent to form a composition containing both agents; oreach agent may be present in separate and distinct compositions whichare administered to the patient simultaneously or at separate times. Forexample, a compound of the invention can be combined with a secondactive agent using conventional procedures and equipment to form acombination of active agents comprising a compound of the invention anda second active agent. Additionally, the active agents may be combinedwith a pharmaceutically acceptable carrier to form a pharmaceuticalcomposition comprising a compound of the invention, a second activeagent and a pharmaceutically acceptable carrier. In this embodiment, thecomponents of the composition are typically mixed or blended to create aphysical mixture. The physical mixture is then administered in atherapeutically effective amount using any of the routes describedherein.

Alternatively, the active agents may remain separate and distinct beforeadministration to the patient. In this embodiment, the agents are notphysically mixed together before administration but are administeredsimultaneously or at separate times as separate compositions. Suchcompositions can be packaged separately or may be packaged together in akit. When administered at separate times, the secondary agent willtypically be administered less than 24 hours after administration of thecompound of the invention, ranging anywhere from concurrent withadministration of the compound of the invention to about 24 hourspost-dose. This is also referred to as sequential administration. Thus,a compound of the invention can be orally administered simultaneously orsequentially with another active agent using two tablets, with onetablet for each active agent, where sequential may mean beingadministered immediately after administration of the compound of theinvention or at some predetermined time later (for example, one hourlater or three hours later). Alternatively, the combination may beadministered by different routes of administration, i.e., one orally andthe other by inhalation.

In one embodiment, the kit comprises a first dosage form comprising acompound of the invention and at least one additional dosage formcomprising one or more of the secondary agents set forth herein, inquantities sufficient to carry out the methods of the invention. Thefirst dosage form and the second (or third, etc,) dosage form togethercomprise a therapeutically effective amount of active agents for thetreatment or prevention of a disease or medical condition in a patient.

Secondary agent(s), when included, are present in a therapeuticallyeffective amount such that they are typically administered in an amountthat produces a therapeutically beneficial effect when co-administeredwith a compound of the invention. The secondary agent can be in the formof a pharmaceutically acceptable salt, solvate, optically purestereoisomer, and so forth. The secondary agent may also be in the formof a prodrug, for example, a compound having a carboxylic acid groupthat has been esterified. Thus, secondary agents listed below areintended to include all such forms, and are commercially available orcan be prepared using conventional procedures and reagents.

In one embodiment, a compound of the invention is administered incombination with a diuretic. Representative diuretics include, but arenot limited to: carbonic anhydrase inhibitors such as acetazolamide anddichlorphenamide; loop diuretics, which include sulfonamide derivativessuch as acetazolamide, ambuside, azosemide, bumetanide, butazolamide,chloraminophenamide, clofenamide, clopamide, clorexolone, disulfamide,ethoxolamide, furosemide, mefruside, methazolamide, piretanide,torsemide, tripamide, and xipamide, as well as non-sulfonamide diureticssuch as ethacrynic acid and other phenoxyacetic acid compounds such astienilic acid, indacrinone and quincarbate; osmotic diuretics such asmannitol; potassium-sparing diuretics, which include aldosteroneantagonists such as spironolactone, and Na⁺ channel inhibitors such asamiloride and triamterene; thiazide and thiazide-like diuretics such asalthiazide, bendroflumethiazide, benzylhydrochlorothiazide,benzthiazide, buthiazide, chlorthalidone, chlorothiazide,cyclopenthiazide, cyclothiazide, epithiazide, ethiazide, fenquizone,flumethiazide, hydrochlorothiazide, hydroflumethiazide, indapamide,methylclothiazide, meticrane, metolazone, paraflutizide, polythiazide,quinethazone, teclothiazide, and trichloromethiazide; and combinationsthereof. In a particular embodiment, the diuretic is selected fromamiloride, bumetanide, chlorothiazide, chlorthalidone, dichlorphenamide,ethacrynic acid, furosemide, hydrochlorothiazide, hydroflumethiazide,indapamide, methylclothiazide, metolazone, torsemide, triamterene, andcombinations thereof. The diuretic will be administered in an amountsufficient to provide from about 5-50 mg per day, more typically 6-25 mgper day, with common dosages being 6.25 mg, 12.5 mg or 25 mg per day.

Compounds of the invention may also be administered in combination witha β₁ adrenergic receptor blocker. Representative β₁ adrenergic receptorblockers include, but are not limited to, acebutolol, alprenolol,amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolol,bisoprolol, bopindolol, bucindolol, bucumolol, bufetolol, bufuralol,bunitrolol, bupranolol, bubridine, butofilolol, carazolol, carteolol,carvedilol, celiprolol, cetamolol, cloranolol, dilevalol, epanolol,esmolol, indenolol, labetolol, levobunolol, mepindolol, metipranolol,metoprolol (e.g., metoprolol succinate and metoprolol tartrate),moprolol, nadolol, nadoxolol, nebivalol, nipradilol, oxprenolol,penbutolol, perbutolol, pindolol, practolol, pronethalol, propranolol,sotalol, sufinalol, talindol, tertatolol, tilisolol, timolol,toliprolol, xibenolol, and combinations thereof. In one particularembodiment, the β₁ adrenergic receptor blocker is selected fromatenolol, bisoprolol, metoprolol, propranolol, sotalol, and combinationsthereof.

In one embodiment, a compound of the invention is administered incombination with a calcium channel blocker. Representative calciumchannel blockers include, but are not limited to, amlodipine, anipamil,aranipine, barnidipine, bencyclane, benidipine, bepridil, clentiazem,cilnidipine, cinnarizine, diltiazem, efonidipine, elgodipine, etafenone,felodipine, fendiline, flunarizine, gallopamil, isradipine, lacidipine,lercanidipine, lidoflazine, lomerizine, manidipine, mibefradil,nicardipine, nifedipine, niguldipine, niludipine, nilvadipine,nimodipine, nisoldipine, nitrendipine, nivaldipine, perhexyline,prenylamine, ryosidine, semotiadil, terodiline, tiapamil, verapamil, andcombinations thereof. In a particular embodiment, the calcium channelblocker is selected from amlodipine, bepridil, diltiazem, felodipine,isradipine, lacidipine, nicardipine, nifedipine, niguldipine,niludipine, nimodipine, nisoldipine, ryosidine, verapamil, andcombinations thereof.

Compounds of the invention can also be administered in combination withan angiotensin-converting enzyme (ACE) inhibitor. Representative ACEinhibitors include, but are not limited to, accupril, alacepril,benazepril, benazeprilat, captopril, ceranapril, cilazapril, delapril,enalapril, enalaprilat, fosinopril, fosinoprilat, imidapril, lisinopril,moexipril, monopril, moveltopril, pentopril, perindopril, quinapril,quinaprilat, ramipril, ramiprilat, saralasin acetate, spirapril,temocapril, trandolapril, zofenopril, and combinations thereof. In aparticular embodiment, the ACE inhibitor is selected from: benazepril,enalapril, lisinopril, ramipril, and combinations thereof.

In one embodiment, a compound of the invention is administered incombination with an AT₁ receptor antagonist, also known as angiotensinII type 1 receptor blockers (ARBs). Representative ARBs include, but arenot limited to, abitesartan, benzyllosartan, candesartan, candesartancilexetil, elisartan, embusartan, enoltasosartan, eprosartan, fonsartan,forasartan, glycyllosartan, irbesartan, isoteoline, losartan, medoximil,milfasartan, olmesartan, opomisartan, pratosartan, ripisartan,saprisartan, saralasin, sarmesin, tasosartan, telmisartan, valsartan,zolasartan, and combinations thereof. In a particular embodiment, theARB is selected from candesartan, eprosartan, irbesartan, losartan,olmesartan, irbesartan, saprisartan, tasosartan, telmisartan, andcombinations thereof. Exemplary salts include eprosartan mesylate,losartan potassium salt, and olmesartan medoxomil. Typically, the ARBwill be administered in an amount sufficient to provide from about 4-600mg per dose, with exemplary daily dosages ranging from 20-320 mg perday.

In another embodiment, a compound of the invention is administered incombination with a neprilysin (NEP) inhibitor. Representative NEPinhibitors include, but are not limited to: candoxatril; candoxatrilat;dexecadotril ((+)-N-[2(R)-(acetylthiomethyl)-3-phenylpropionyl]glycinebenzyl ester); CGS-24128(3-[3-(biphenyl-4-yl)-2-(phosphono-methylamino)propionamido]propionicacid); CGS-24592((S)-3-[3-(biphenyl-4-yl)-2-(phosphonomethylamino)propionamido]propionicacid); CGS-25155 (N-[9(R)-(acetyl-thiomethyl)-10-oxo-1-azacyclodecan-2(S)-ylcarbonyl]-4(R)-hydroxy-L-proline benzyl ester);3-(1-carbamoylcyclohexyl)propionic acid derivatives described in WO2006/027680 to Hepworth et al. (Pfizer Inc.); JMV-390-1(2(R)-benzyl-3-(N-hydroxycarbamoyl)-propionyl-L-isoleucyl-L-leucine);ecadotril; phosphoramidon; retrothiorphan; RU-42827(2-(mercaptomethyl)-N-(4-pyridinyl)benzenepropionamide); RU-44004(N-(4-morpholinyl)-3-phenyl-2-(sulfanylmethyl)propionamide); SCH-32615((S)—N—[N-(1-carboxy-2-phenylethyl)-L-phenylalanyl]-β-alanine) and itsprodrug SCH-34826((S)—N—[N-[1-[[(2,2-dimethyl-1,3-dioxolan-4-yl)methoxy]carbonyl]-2-phenylethyl]-L-phenylalanyl]-O-alanine);sialorphin; SCH-42495(N-[2(S)-(acetylsulfanylmethyl)-3-(2-methylphenyl)-propionyl]-L-methionineethyl ester); spinorphin; SQ-28132(N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]leucine); SQ-28603(N-[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]-β-alanine); SQ-29072(7-[[2-(mercaptomethyl)-1-oxo-3-phenylpropyl]amino]heptanoic acid);thiorphan and its prodrug racecadotril; UK-69578(cis-4-[[[1-[2-carboxy-3-(2-methoxyethoxy)propyl]cyclopentyl]carbonyl]amino]cyclohexanecarboxylicacid); UK-447,841(2-{1-[3-(4-chlorophenyl)propylcarbamoyl]-cyclopentylmethyl}-4-methoxy-butyricacid); UK-505,749((R)-2-methyl-3-{1-[3-(2-methylbenzothiazol-6-yl)propyl-carbamoyl]cyclopentyl}propionicacid); 5-biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methylpentanoicacid and 5-biphenyl-4-yl-4-(3-carboxypropionylamino)-2-methyl-pentanoicacid ethyl ester (WO 2007/056546); daglutril[(3S,2′R)-3-{1-[2′-(ethoxy-carbonyl)-4′-phenylbutyl]-cyclopentan-1-carbonylamino}-2,3,4,5-tetrahydro-2-oxo-1H-1-benzazepine-1-aceticacid] described in WO 2007/106708 to Khder et al. (Novartis AG); andcombinations thereof. In a particular embodiment, the NEP inhibitor isselected from candoxatril, candoxatrilat, CGS-24128, phosphoramidon,SCH-32615, SCH-34826, SQ-28603, thiorphan, and combinations thereof. TheNEP inhibitor will be administered in an amount sufficient to providefrom about 20-800 mg per day, with typical daily dosages ranging from50-700 mg per day, more commonly 100-600 or 100-300 mg per day.

In yet another embodiment, a compound of the invention is administeredin combination with a non-steroidal anti-inflammatory agent (NSAID).Representative NSAIDs include, but are not limited to: acemetacin,acetyl salicylic acid, alclofenac, alminoprofen, amfenac, amiprilose,amoxiprin, anirolac, apazone, azapropazone, benorilate, benoxaprofen,bezpiperylon, broperamole, bucloxic acid, carprofen, clidanac,diclofenac, diflunisal, diftalone, enolicam, etodolac, etoricoxib,fenbufen, fenclofenac, fenclozic acid, fenoprofen, fentiazac, feprazone,flufenamic acid, flufenisal, fluprofen, flurbiprofen, furofenac,ibufenac, ibuprofen, indomethacin, indoprofen, isoxepac, isoxicam,ketoprofen, ketorolac, lofemizole, lornoxicam, meclofenamate,meclofenamic acid, mefenamic acid, meloxicam, mesalamine, miroprofen,mofebutazone, nabumetone, naproxen, niflumic acid, oxaprozin, oxpinac,oxyphenbutazone, phenylbutazone, piroxicam, pirprofen, pranoprofen,salsalate, sudoxicam, sulfasalazine, sulindac, suprofen, tenoxicam,tiopinac, tiaprofenic acid, tioxaprofen, tolfenamic acid, tolmetin,triflumidate, zidometacin, zomepirac, and combinations thereof. In aparticular embodiment, the NSAID is selected from etodolac,flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, meloxicam,naproxen, oxaprozin, piroxicam, and combinations thereof.

In yet another embodiment, a compound of the invention is administeredin combination with an anti-lipid agent. Representative anti-lipidagents include, but are not limited to, statins such as atorvastatin,fluvastatin, lovastatin, pravastatin, rosuvastatin and simvastatin;cholesteryl ester transfer proteins (CETPs); and combinations thereof.

In yet another embodiment, a compound of the invention is administeredin combination with an anti-diabetic agent. Representative anti-diabeticagents include, but are not limited to: injectable drugs such as insulinand insulin derivatives; orally effective drugs including biguanidessuch as metformin, glucagon antagonists, α-glucosidase inhibitors suchas acarbose and miglitol, meglitinides such as repaglinide,oxadiazolidine-diones, sulfonylureas such as chlorpropamide,glimepiride, glipizide, glyburide, and tolazamide, thiazolidinedionessuch as pioglitazone, and rosiglitazone; and combinations thereof.

In one embodiment, a compound of the invention is administered incombination with an anti-thrombotic agent. Representativeanti-thrombotic agents include, but are not limited to, aspirin,anti-platelet agents, heparin, and combinations thereof. Compounds ofthe invention may also be administered in combination with a renininhibitor, examples of which include, but are not limited to, aliskiren,enalkiren, remikiren, and combinations thereof. In another embodiment, acompound of the invention is administered in combination with anendothelin receptor antagonist, representative examples of whichinclude, but are not limited to, bosentan, darusentan, tezosentan, andcombinations thereof. Compounds of the invention may also beadministered in combination with an endothelin converting enzymeinhibitor, examples of which include, but are not limited to,phosphoramidon, CGS 26303, and combinations thereof. In yet anotherembodiment, a compound of the invention is administered in combinationwith an aldosterone antagonist, representative examples of whichinclude, but are not limited to, eplerenone, spironolactone, andcombinations thereof.

Combined therapeutic agents may also be helpful in further combinationtherapy with compounds of the invention. For example, a combination ofthe ACE inhibitor enalapril (in the maleate salt form) and the diuretichydrochlorothiazide, which is sold under the mark Vaseretic®, or acombination of the calcium channel blocker amlodipine (in the besylatesalt form) and the ARB olmesartan (in the medoxomil prodrug form), or acombination of a calcium channel blocker and a statin, all may also beused with the compounds of the invention. Dual-acting agents may also behelpful in combination therapy with compounds of the invention. Forexample, angiotensin-converting enzyme/neprilysin (ACE/NEP) inhibitorssuch as: AVE-0848((4S,7S,12bR)-7-[3-methyl-2(S)-sulfanylbutyramido]-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylicacid); AVE-7688 (ilepatril) and its parent compound; BMS-182657(2-[2-oxo-3(S)-[3-phenyl-2(S)-sulfanylpropionamido]-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]aceticacid); CGS-26303([N-[2-(biphenyl-4-yl)-1(S)-(1H-tetrazol-5-yl)ethyl]amino]-methylphosphonicacid); CGS-35601(N-[1-[4-methyl-2(S)-sulfanylpentanamido]-cyclopentylcarbonyl]-L-tryptophan);fasidotril; fasidotrilate; enalaprilat; ER-32935((3R,6S,9aR)-6-[3(S)-methyl-2(S)-sulfanylpentanamido]-5-oxoperhydrothiazolo[3,2-a]azepine-3-carboxylicacid); gempatrilat; MDL-101264((4S,7S,12bR)-7-[2(S)-(2-morpholinoacetylthio)-3-phenylpropionamido]-6-oxo-1,2,3,4,6,7,8,12b-octahydro-pyrido[2,1-a][2]benzazepine-4-carboxylicacid); MDL-101287([4S-[4α,7α(R*),12bβ]]-7-[2-(carboxymethyl)-3-phenylpropionamido]-6-oxo-1,2,3,4,6,7,8,12b-octahydropyrido[2,1-a][2]benzazepine-4-carboxylicacid); omapatrilat; RB-105(N-[2(S)-(mercaptomethyl)-3(R)-phenylbutyl]-L-alanine); sampatrilat;SA-898((2R,4R)—N-[2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)thiazolidin-4-ylcarbonyl]-L-phenylalanine);Sch-50690(N-[1(S)-carboxy-2-[N2-(methanesulfonyl)-L-lysylamino]ethyl]-L-valyl-L-tyrosine);and combinations thereof, may also be included. In one particularembodiment, the ACE/NEP inhibitor is selected from: AVE-7688,enalaprilat, fasidotril, fasidotrilate, omapatrilat, sampatrilat, andcombinations thereof.

Other therapeutic agents such as α₂-adrenergic receptor agonists andvasopressin receptor antagonists may also be helpful in combinationtherapy. Exemplary α₂-adrenergic receptor agonists include clonidine,dexmedetomidine, and guanfacine. Exemplary vasopressin receptorantagonists include tolvaptan.

The following formulations illustrate representative pharmaceuticalcompositions of the invention.

Exemplary Hard Gelatin Capsules For Oral Administration

A compound of the invention (50 g), 440 g spray-dried lactose and 10 gmagnesium stearate are thoroughly blended. The resulting composition isthen loaded into hard gelatin capsules (500 mg of composition percapsule). Alternately, a compound of the invention (20 mg) is thoroughlyblended with starch (89 mg), microcrystalline cellulose (89 mg) andmagnesium stearate (2 mg). The mixture is then passed through a No. 45mesh U.S. sieve and loaded into a hard gelatin capsule (200 mg ofcomposition per capsule).

Exemplary Gelatin Capsule Formulation For Oral Administration

A compound of the invention (100 mg) is thoroughly blended withpolyoxyethylene sorbitan monooleate (50 mg) and starch powder (250 mg).The mixture is then loaded into a gelatin capsule (300 mg of compositionper capsule).

Alternately, a compound of the invention (40 mg) is thoroughly blendedwith microcrystalline cellulose (Avicel PH 103; 260 mg) and magnesiumstearate (0.8 mg). The mixture is then loaded into a gelatin capsule(Size #1, White, Opaque) (300 mg of composition per capsule).

Exemplary Tablet Formulation For Oral Administration

A compound of the invention (10 mg), starch (45 mg) and microcrystallinecellulose (35 mg) are passed through a No. 20 mesh U.S. sieve and mixedthoroughly. The granules so produced are dried at 50-60° C. and passedthrough a No. 16 mesh U.S. sieve. A solution of polyvinylpyrrolidone (4mg as a 10% solution in sterile water) is mixed with sodiumcarboxymethyl starch (4.5 mg), magnesium stearate (0.5 mg), and talc (1mg), and this mixture is then passed through a No. 16 mesh U.S. sieve.The sodium carboxymethyl starch, magnesium stearate and talc are thenadded to the granules. After mixing, the mixture is compressed on atablet machine to afford a tablet weighing 100 mg.

Alternately, a compound of the invention (250 mg) is thoroughly blendedwith microcrystalline cellulose (400 mg), silicon dioxide fumed (10 mg),and stearic acid (5 mg). The mixture is then compressed to form tablets(665 mg of composition per tablet).

Alternately, a compound of the invention (400 mg) is thoroughly blendedwith cornstarch (50 mg), croscarmellose sodium (25 mg), lactose (120mg), and magnesium stearate (5 mg). The mixture is then compressed toform a single-scored tablet (600 mg of composition per tablet).

Alternately, a compound of the invention (100 mg) is thoroughly blendedwith cornstarch (100 mg) with an aqueous solution of gelatin (20 mg).The mixture is dried and ground to a fine powder. Microcrystallinecellulose (50 mg) and magnesium stearate (5 mg) are the admixed with thegelatin formulation, granulated and the resulting mixture compressed toform tablets (100 mg of active per tablet).

Exemplary Suspension Formulation For Oral Administration

The following ingredients are mixed to form a suspension containing 100mg of active agent per 10 mL of suspension:

Ingredients Amount Compound of the invention 1.0 g Fumaric acid 0.5 gSodium chloride 2.0 g Methyl paraben 0.15 g Propyl paraben 0.05 gGranulated sugar 25.5 g Sorbitol (70% solution) 12.85 g Veegum ® K(magnesium aluminum silicate) 1.0 g Flavoring 0.035 mL Colorings 0.5 mgDistilled water q.s. to 100 mL

Exemplary Liquid Formulation For Oral Administration

A suitable liquid formulation is one with a carboxylic acid-based buffersuch as citrate, lactate and maleate buffer solutions. For example, acompound of the invention (which may be pre-mixed with DMSO) is blendedwith a 100 mM ammonium citrate buffer and the pH adjusted to pH 5, orwith is blended with a 100 mM citric acid solution and the pH adjustedto pH 2. Such solutions may also include a solubilizing excipient suchas a cyclodextrin, for example the solution may include 10 wt %hydroxypropyl-β-cyclodextrin.

Other suitable formulations include a 5% NaHCO₃ solution, with orwithout cyclodextrin.

Exemplary Injectable Formulation For Administration by Injection

A compound of the invention (0.2 g) is blended with 0.4 M sodium acetatebuffer solution (2.0 mL). The pH of the resulting solution is adjustedto pH 4 using 0.5 N aqueous hydrochloric acid or 0.5 N aqueous sodiumhydroxide, as necessary, and then sufficient water for injection isadded to provide a total volume of 20 mL. The mixture is then filteredthrough a sterile filter (0.22 micron) to provide a sterile solutionsuitable for administration by injection.

Exemplary Compositions For Administration by Inhalation

A compound of the invention (0.2 mg) is micronized and then blended withlactose (25 mg). This blended mixture is then loaded into a gelatininhalation cartridge. The contents of the cartridge are administeredusing a dry powder inhaler, for example.

Alternately, a micronized compound of the invention (10 g) is dispersedin a solution prepared by dissolving lecithin (0.2 g) in demineralizedwater (200 mL). The resulting suspension is spray dried and thenmicronized to form a micronized composition comprising particles havinga mean diameter less than about 1.5 μm. The micronized composition isthen loaded into metered-dose inhaler cartridges containing pressurized1,1,1,2-tetrafluoroethane in an amount sufficient to provide about 10 μgto about 500 μg of the compound of the invention per dose whenadministered by the inhaler.

Alternately, a compound of the invention (25 mg) is dissolved in citratebuffered (pH 5) isotonic saline (125 mL). The mixture is stirred andsonicated until the compound is dissolved. The pH of the solution ischecked and adjusted, if necessary, to pH 5 by slowly adding aqueous 1Nsodium hydroxide. The solution is administered using a nebulizer devicethat provides about 10 μg to about 500 μg of the compound of theinvention per dose.

EXAMPLES

The following Preparations and Examples are provided to illustratespecific embodiments of the invention. These specific embodiments,however, are not intended to limit the scope of the invention in any wayunless specifically indicated.

The following abbreviations have the following meanings unless otherwiseindicated and any other abbreviations used herein and not defined havetheir standard meaning:

ACE angiotensin converting enzyme APP aminopeptidase P AT₁ angiotensinII type 1 (receptor) AT₂ angiotensin II type 2 (receptor) BSA bovineserum albumin DCM dichloromethane DIPEA N,N-diisopropylethylamine DMFN,N-dimethylformamide DMSO dimethyl sulfoxide Dnp 2,4-dinitrophenyl DOCAdeoxycorticosterone acetate EDCN-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride EDTAethylenediaminetetraacetic acid

Any other abbreviations used herein but not defined have their standard,generally accepted meaning. Unless noted otherwise, all materials, suchas reagents, starting materials and solvents, were purchased fromcommercial suppliers (such as Sigma-Aldrich, Fluka Riedel-de Haën, andthe like) and were used without further purification.

Preparation 1 7-Methyl-2-propyl-3H-benzoimidazole-5-carboxylic AcidMethyl Ester

7-Methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid (30.0 g, 137 mmol)was dissolved in MeOH (550 mL) and added to a round bottom flask,followed by the addition of 20 mL of a hydrogen chloride solution(30:70, conc. HCl:water). The mixture was refluxed for 12 hours thenconcentrated under reduced pressure to afford the title compound as ayellow solid (31.8 g, 137 mmol). MS m/z: [M+H⁺] calcd for C₁₃H₁₆N₂O₂,233.12. found 233.2.

Preparation 2 4′-Bromomethylbiphenyl-2-carboxylic Acid t-Butyl Ester

A solution of 4′-methylbiphenyl-2-carboxylic acid (48.7 g, 230 mmol) andthionyl chloride (150 mL) was stirred at room temperature. After 5.5hours, the mixture was concentrated in vacuo. Excess thionyl chloridewas removed by co-distillation with toluene to afford a yellow solid(52.6 g). The solid was then dissolved in THF (500 mL) and cooled to 0°C. Potassium t-butoxide (15.0 g, 0.13 mol) was added portion wise,followed by addition of a 1M solution of potassium t-butoxide in THF(250 mL). Additional solid potassium t-butoxide (21.4 g, 100 mmol) wasadded and the mixture was stirred at 0° C. for 1.5 hours. The mixturewas then partitioned between EtOAc and water. The organic layer waswashed with saturated aqueous NaCl, dried over MgSO₄, filtered, andconcentrated to afford 4′-methylbiphenyl-2-carboxylic acid t-butyl ester(62.3 g) as a yellow oil, which was used directly in the next step.

This oil (62 g, 230 mmol), benzoyl peroxide (3.9 g, 16.0 mmol), and NBS(41.2 g, 230 mmol) were mixed with benzene (800 mL) and heated toreflux. After 4.5 hours, benzoyl peroxide (1 g) was added, followed byNBS (16 g, 66.0 mmol) 30 minutes later. The mixture was stirred for atotal of 6 hours, then cooled, filtered, and concentrated in vacuo. Theresulting residue was crystallized from diethyl ether and hexane at 4°C. overnight to give the title compound (40.7 g) as a pale yellow solid.

¹H NMR (DMSO) δ (ppm) 1.1 (s, 9H), 4.6 (s, 2H), 7.1-7.6 (m, 8H).

Preparation 33-(2′-t-Butoxycarbonylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicAcid

3-(2′-t-Butoxycarbonylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid methyl ester (3a): A solution of7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid methyl ester (10.0g, 43 mmol; prepared as described in Preparation 1) in DMF (300 mL) wascooled in an ice bath. Sodium hydride (4.5 g, 60 wt % in mineral oil)was slowly added over 5 minutes. 4′-Bromomethylbiphenyl-2-carboxylicacid t-butyl ester (15.7 g, 45.2 mmol; purchased from commercial sourceor prepared as described in Preparation 2) was then added. The mixturewas gradually warmed to room temperature, then stirred at 75° C.overnight. The mixture was then cooled and concentrated in vacuo and theresultant residue was partitioned between saturated aqueous NaCl andEtOAc (1:1, 400 mL). The organic layer was collected, dried over MgSO₄and evaporated to dryness, yielding Intermediate (3a) as a pale yellowoil (16.0 g, 32.1 mmol). MS m/z: [M+H⁺] calcd for C₃₁H₃₄N₂O₄, 499.25.found 499.5.

Intermediate (3a) (9.0 g, 18.1 mmol) and THF (100 mL) were added to around bottom flask. 1 M NaOH in water (90 mL) was added and the mixturewas stirred at room temperature overnight. The mixture was acidified toa pH of 4 with 1M HCl. The solution was then extracted three times withEtOAc, and concentrated under reduced pressure to afford the crude titlecompound as a yellow solid. MS m/z: [M+H⁺] calcd for C₃₀H₃₂N₂O₄, 485.24.found 485.4.

Preparation 4 ((R)-1-Benzyl-2-hydroxycarbamoylethyl)carbamic Acidt-Butyl Ester

DIPEA (32.7 mL, 188 mmol) and EDC (15.4 g, 80.5 mmol) were added to asolution of (R)-3-t-butoxycarbonylamino-4-phenylbutyric acid (15.0 g,53.7 mmol), HOBt (7.3 g, 53.7 mmol), and hydroxylamine hydrochloride(7.5 g, 107 mmol) in DMF (150 mL). The mixture was stirred at roomtemperature for 1 day and then concentrated in vacuo to yield a paleyellow oil. The oil was distributed between 5% THF in EtOAc and IMphosphoric acid. The organic layer was collected and washed with 1MNaOH. The alkaline aqueous layer was then acidified using 1M phosphoricacid and extracted with EtOAc. The organic layer was evaporated and theresidue was purified by silica gel chromatography (0-100% EtOAc inhexanes) to afford the title compound as a white solid (1.0 g, 3.4mmol). MS m/z: [M+H⁺] calcd for C₁₅H₂₂N₂O₄, 295.16. found 295.2.

Example 14′-[6-((R)-1-Benzyl-2-hydroxycarbamoylethylcarbamoyl)-4-methyl-2-propylbenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicAcid t-Butyl Ester (1a: R^(1a)=butyl) and4′-[6-((R)-1-Benzyl-2-hydroxycarbamoylethylcarbamoyl)-4-methyl-2-propylbenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicAcid (1b; R^(1a)═H)

To a solution of (R)-1-benzyl-2-hydroxycarbamoylethyl)carbamic acidt-butyl ester (2.8 g, 9.5 mmol; prepared as described in Preparation 4)was added methylene chloride (20 mL) and TFA (30 mL). The mixture wasstirred at room temperature for 30 minutes and concentrated to drynessunder reduced pressure. The solids were dissolved in DMF (60 mL),followed by the addition of3-(2′-t-butoxycarbonylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid (2.6 g, 5.4 mmol; prepared as described in Preparation 3), HOBt(1.3 g, 10 mmol), EDC (1.8 g, 10 mmol;), and DIPEA (3.9 mL, 22.4 mmol).The final mixture was stirred at room temperature overnight, thenconcentrated under reduced pressure. The residue was dissolved in EtOAcand washed with 1M phosphoric acid, and then a saturated solution ofsodium bicarbonate. The organic layer was then concentrated underreduced pressure and purified by reverse phase:chromatography (1:1water:acetonitrile with 0.1% TFA) to obtain compound (1a) as the TFAsalt (282 mg, 364 μmol). MS m/z: [M+H⁺] calcd for C₄₀H₄₄N₄O₅, 661.33.found 661.4.

Compound (1a) (282 mg, 364 μmol) was dissolved in methylene chloride (5mL). TFA (10 mL) was added and the mixture was stirred at roomtemperature for 2 hours then concentrated in vacuo and purified byreverse phase HPLC (1:1 water/acetonitrile with 0.1% TFA) to obtaincompound (1b) as the TFA salt (190 mg, 265 μmol). MS m/z: [M+H⁺] calcdfor C₃₆H₃₆N₄O₅, 605.27. found 605.6.

¹H NMR (400 Mz, CD₃OD) δ (ppm) 1.04 (t, 3H, J=5 Hz), 1.35 (m, 2H), 1.80(q, 2H, J=5 Hz), 2.43 (m, 2H), 2.67 (s, 3H), 2.94 (d, 2H, J=5 Hz), 3.19(m, 1H), 5.76 (m, 2H), 7.11 (m, 2H, J=5 Hz), 7.22 (m, 5H), 7.33 (m, 2H),7.44 (m, 1H), 7.53 (m, 1H), 7.69 s, 1H), 7.81 (m, 1H), 7.87 (s, 1H).

Preparation 5(R)-2-((R)-2-Amino-3-phenylpropyldisulfanyl)-1-benzylethylamine-2[HCl]

Diisopropyl azodicarboxylate (23.5 mL, 119 mmol) was added to a solutionof triphenylphosphine (31.3 g, 119 mmol) in THF (600 mL), cooled in anice bath. The solution was stirred for 30 minutes, and a white solid wasformed. ((R)-1-Benzyl-2-hydroxyethyl)carbamic acid t-butyl (20.0 g, 80mmol) and thioacetic acid (8.5 mL, 120 mmol) was added. The finalmixture was stirred at 0° C. for 1 hour, then stirred at roomtemperature overnight. The mixture was stripped and diluted with EtOAc(400 mL), and washed with a cold saturated NaHCO₃ solution. The organiclayer was dried over MgSO₄, and the filtrate was evaporated to dryness,yielding a pale brown oil. The material was flash chromatographed 30-80%EtOAc:Hex recovering Intermediate (5a) as a brown oil.

Intermediate (5a) was dissolved in 200 mL THF, followed by the additionof 1M lithium hydroxide in water (398 mL). Air was bubbled vigorouslythrough the solution for 1 hour followed by the addition of 100 mL THF.The air stream was then removed and the mixture was stirred at roomtemperature for 24 hours. The solution was then acidified to pH˜5 withacetic acid, and the THF was removed in vacuo. The precipitate wasfiltered and rinsed with 50 mL deionized water, producing the dimer(Intermediate 5b). The solid was transferred to a round bottom flask,suspended in 100 mL MeCN, and then concentrated under reduced pressureto remove excess water. The recovered Intermediate 5b was dissolved in4.0 M of HCl in 1,4-dioxane (150 mL) and stirred at room temperature.After 2 hours, the mixture was concentrated under reduced pressure andthe material was triturated with EtOAc. The resulting white solid wasfiltered, washed with 60 mL EtOAc, and dried in vacuo to yield 8.5 g ofthe title compound. MS m/z: [M+H⁺] calcd for C₁₈H₂₄N₂S₂ 333.1. found333.4.

¹H NMR (CD₃OD) δ (ppm): 2.7 (m, 2H), 2.9 (m, 1H), 3.0 (m, 1H), 3.7 (m,1H), 7.2-7.4 (m, 5H).

Example 24′-[6-((R)-1-Benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propylbenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicAcid t-Butyl Ester (2a) and4′-[6-((R)-1-Benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propylbenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicAcid (2b)

3-(2′-t-butoxycarbonylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid (727 mg, 1.5 mmol; prepared as described in Preparation 3) wasdissolved into 30 mL DMF. HATU (570 mg, 1.5 mmol) was added and themixture was stirred for 10 minutes.(R)-2-((R)-2-Amino-3-phenylpropyldisulfanyl)-1-benzylethylamine-2-[HCl](304 mg, 0.75 mmol; prepared as described in Preparation 5) was added,followed by the addition of DIPEA (522 μL, 3.0 mmol). The mixture wasstirred at room temperature for 5 minutes then warmed to 45° C. After 2hours, the mixture was cooled to room temperature and partitionedbetween 100 mL EtOAc and 60 mL 10% LiCl (aqueous). The organic layer wasthen washed with a saturated NaHCO₃ solution and saturated aqueous NaCl,dried over MgSO₄ and concentrated. The recovered material (1.2 g, 950mmol; dimer intermediate) was dissolved in THF (30 mL, 0.4 mol). Asolution of tris(2-carboxyethyl)phosphine hydrochloride (1.4 g, 4.8mmol) in water (5.0 mL) was added, and the mixture was stirred at roomtemperature for 1 hour. The mixture was then quenched with 1 mL aceticacid and diluted with 50 mL EtOAc and 10 mL water. The layers wereseparated and the organic was washed with saturated aqueous NaCl. EtOAcwas removed in vacuo recovering Compound (2a) as an oil, which wasimmediately dissolved in 30 mL of 30% TFA:DCM and stirred for 2 hours atroom temperature. The mixture was concentrated and purified bypreparative HPLC to provide Compound (2b) as a white powder (365 mg). MSm/z: [M+H⁺] calcd for C₃₅H₃₅N₃O₃S, 578.24. found 578.5.

¹H NMR (CD₃OD) δ (ppm): 1.0 (t, 3H), 1.8 (m, 2H), 2.6-2.8 (m, 5H), 3.9(m, 1H), 3.1 (m, 1H), 3.2 (t, 2H), 4.3 (m, 1H), 5.8 (s, 2H), 7.1 (d,1H), 7.1-7.3 (m, 6H), 7.3-7.4 (m, 3H), 7.4-7.5 (m, 1H), 7.5-7.6 (m, 1H),7.5-7.6 (m, 1H), 7.7 (s, 1H), 7.8 (d, 1H), 7.9 (s, 1H).

Preparation 6 4-Bromomethyl-2-fluorobenzoic acid Methyl Ester

2-Fluoro-4-methylbenzoic acid methyl ester (6a):2-Fluoro-4-methylbenzoic acid (30.0 g, 195 mmol) was dissolved in MeOH(600 mL, 10 mol), and 12 M HCl (3.2 mL, 39 mmol) was added. The mixturewas heated to reflux and stirred for 48 hours, then cooled andconcentrated. The recovered material was dried in vacuo for 24 hours toobtain Intermediate (6a) as a white solid that was used without furtherpurification.

Intermediate (6a) (32 g, 188 mmol), NBS (33.5 g, 188 mmol), and benzoylperoxide (0.46 g, 1.9 mmol) were dissolved in benzene (550 mL, 6.2 mol)and heated to reflux for 20 hours. The mixture was cooled to roomtemperature, filtered and concentrated. The residue was flashchromatographed to produce the title compound as a white solid (23.6 g).

¹H NMR (CDCl₃) δ (ppm): 3.9 (s, 3H), 4.4 (s, 2H), 7.1-7.4 (m, 2H), 7.8(t, 1H).

Preparation 7 (7-Methyl-2-propyl-3H-benzoimidazol-5-yl)methanol

7-Methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid methyl ester (7a):Sulfuric acid (12 mL, 0.22 mol) was added to7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid (30 g, 136 mmol)dissolved in MeOH (670 mL, 16 mol). The mixture was refluxed for 36hours and concentrated in vacuo. The recovered material was dissolved in500 mL EtOAc and washed with a saturated NaHCO₃ solution. The organiclayer was dried over MgSO₄ and concentrated to provide Intermediate (7a)as a brown solid (29.1 g). MS m/z: [M+H⁺] calcd for C₁₃H₁₆N₂O₂, 233.1.found 233.2.

1M LiAlH₄ in THF (380 mL, 380 mmol) was added to a round bottom flaskthat had been oven dried and cooled under nitrogen. The solution wascooled to 0° C. and stirred under nitrogen. A solution of Intermediate(7a) (29.2 g, 125 mmol) in THF (100 mL) was added dropwise via anaddition funnel and the mixture was stirred at 0° C. After 1 hour, themixture was warmed to room temperature and stirred overnight. Themixture was cooled to 0° C. EtOAc (50 mL) was slowly added to quench theremaining LiAlH₄. The reaction was then quenched with 70 mL of saturatedNH₄Cl. The mixture was washed with EtOAc (400 mL) and the layers wereseparated. The organic layer was dried over MgSO₄ and concentrated,recovering a brown solid that was flash chromatographed in 5% MeOH:EtOActo produce the title compound as a white foam (18.4 g).

¹H NMR (CD₃OD) δ (ppm): 1.1 (t, 3H), 1.9 (m, 2H), 2.6 (s, 3H), 2.9 (t,2H), 4.7 (s, 2H), 7.0 (s, 1H), 7.4 (s, 1H).

Preparation 84-(6-Aminomethyl-4-methyl-2-propylbenzoimidazol-1-ylmethyl)-2-fluorobenzoicAcid Methyl Ester

2-Fluoro-4-(6-hydroxymethyl-4-methyl-2-propyl-benzoimidazol-1-ylmethyl)-benzoicacid methyl ester (8a):(7-Methyl-2-propyl-3H-benzoimidazol-5-yl)methanol (3 g, 15 mmol;prepared as described in Preparation 7) was dissolved in 20 mL of dryDMF. The solution was cooled to 0° C. and sodium hydride (598 mg, 15mmol, 60 wt % in mineral oil) was added. The mixture was stirred for 30minutes. 4-Bromomethyl-2-fluorobenzoic acid methyl ester (3.7 g, 15mmol; prepared as described in Preparation 3) in 50 mL of DMF was added,and the mixture was warmed to room temperature and stirred for 10minutes. The solution was partitioned between EtOAc (300 mL) and 150 mL10% LiCl (aqueous). The organic layer was separated, dried over MgSO₄and concentrated. The concentrate was flash chromatographed to produceIntermediate (8a) as a clear oil (2.4 g). MS m/z: [M+H⁺] calcd forC₂₁H₂₃FN₂O₃, 371.7. found 371.0.

4-(6-Azidomethyl-4-methyl-2-propylbenzoimidazol-1-ylmethyl)-2-fluorobenzoicacid methyl ester (8b): Intermediate (8a) (2.4 g, 6.5 mmol) was added to125 mL of DCM followed by DIPEA (4.6 mL, 26.1 mmol) and4-dimethylaminopyridine (80 mg, 653 μmol). Methanesulfonyl chloride (1.0mL, 13.1 mmol) was then added at 0° C. and the mixture was warmed toroom temperature. After 3 hours, the mixture was concentrated and thematerial redissolved in 40 mL DMF. Sodium azide (467 mg, 7.2 mmol) wasadded and the mixture was heated at 80° C. for 1 hour. The mixture wasthen cooled to room temperature. The solution was partitioned betweenEtOAc (100 mL) and 50 mL 10% LiCl (aqueous). The organic layer wasconcentrated and flash chromatographed 20-70% EtOAc:hexanes to yieldIntermediate (8b) as a yellow oil (2.1 g). MS m/z: [M+H⁺] calcd forC₂₁H₂₂FN₅O₂, 396.2. found 396.0.

Intermediate (8b) (1.9 g, 4.9 mmol) was dissolved in THF (24 mL).Triphenylphosphine (1.7 g, 6.3 mmol) was added and the mixture wasstirred at room temperature for 30 minutes. Water (175 μL, 9.7 mmol) wasadded and the mixture was heated to 60° C. After 3 hours, the mixturewas cooled to room temperature and concentrated in vacuo. Theconcentrate was dissolved in EtOAc (50 mL) and washed twice in 30 mL 1NHCl. The aqueous layer was extracted with EtOAc (50 mL) then basified topH˜10 with 6N NaOH. The solution was saturated with NaCl, extracted fourtimes with 50 mL DCM and dried over MgSO₄. The organic layer was thenconcentrated to provide the title compound (1.8 g), which was usedwithout further purification.

¹H NMR (CD₃OD) δ (ppm): 0.9 (t, 3H), 1.7 (m, 2H), 2.6 (s, 3H), 2.8 (t,2H), 4.8 (s, 2H), 4.9 (s, 3H), 5.6 (s, 2H), 6.9 (m, 2H), 7.0 (s, 1H),7.1 (s, 1H), 7.8 (t, 1H).

Preparation 9 (S)-2-Acetylsulfanyl-4-methylpentanoic Acid

(R)-2-Bromo-4-methylpentanoic acid (9a): D-Leucine (9.9 g, 75.2 mmol)was dissolved in 3M HBr in water (120 mL) and cooled to 0° C. A solutionof sodium nitrite (8.3 g, 120 mmol) in water (20 mL, 100 mmol) wasadded. The mixture was stirred at 0° C. for 2.5 hours, extracted twicewith EtOAc, washed twice with saturated aqueous NaCl, dried over MgSO₄,filtered, and concentrated to afford 12.6 g (86%) of Intermediate (9a)as a pale yellow oil. This was taken on to the next step without furtherpurification.

¹H NMR (DMSO) 4.31 (1H, t), 1.75 (2H, m) 1.65 (1H, m) 0.82 (6H, dd).

Intermediate (9a) (12.5 g, 64.1 mmol), potassium thioacetate (11.0 g,96.1 mmol), and DMF (100 mL, 1.0 mol) were added to a round bottomflask, and the mixture stirred at room temperature for 1 hour. Water(100 mL) was added, and the mixture extracted three times with EtOAc,washed twice with saturated aqueous NaCl, dried over MgSO₄, filtered,and concentrated. The product was purified by silica gel chromatography(0-40% EtOAc: hexanes with 5% acetic acid) to yield the title compound(6.8 g) as a pale yellow oil.

¹H NMR (DMSO) 3.96 (1H, t), 2.45 (3H, s), 1.70 (1H, m), 1.55 (1H, m),1.42 (1H, m), 0.84 (6H, dd).

Example 34-{6-[((S)-2-Acetylsulfanyl-4-methylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}-2-fluorobenzoicAcid Methyl Ester (3a; R^(1a)═CH₃; R^(5a)═—C(O)CH₃) and2-Fluoro-4-{6-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicAcid (3b; R^(1a)═R^(5a)═H)

(S)-2-Acetylsulfanyl-4-methylpentanoic acid (19.0 mg, 0.10 mmol;prepared as described in Preparation 9) was dissolved in DMF (1.0 mL),followed by the addition of EDC (19.1 mg, 100 μmol) and HOBt (13.5 mg,0.1 mmol). The solution was stirred for 30 minutes.4-(6-Aminomethyl-4-methyl-2-propylbenzoimidazol-1-ylmethyl)-2-fluorobenzoicacid methyl ester (36.9 mg, 0.1 mmol; prepared as described inPreparation 8) in DMF (0.5 mL) was added, followed by the addition ofDIPEA (17.4 μL, 0.1 mmol), and the mixture was stirred for 20 hours toyield Compound (3a). The mixture was concentrated under reduced pressureand then redissolved in MeOH (1 mL). 3N NaOH (750 μL, 23 mmol) wasadded, under nitrogen, and the mixture was stirred for 3 hours. Themixture was then acidified with 6N HCl (0.5 mL, 30 mmol), concentratedunder reduced pressure and then purified by preparative HPLC to yieldCompound (3b) as a white solid (0.03 g, 50%). MS m/z: [M+H⁺] calcd forC₂₁H₂₂FN₅O₂, 486.2. found 486.2.

Preparation 104′-(6-Amino-4-methyl-2-propylbenzoimidazol-1-ylmethyl)biphenyl-2-carboxylicAcid

4′-(6-Azidocarbonyl-4-methyl-2-propylbenzoimidazol-1-ylmethyl)biphenyl-2-carboxylicacid t-butyl ester (10a): DIPEA (0.43 mL, 25 mmol) anddiphenylphosphonic azide (489 μL, 2.3 mmol) were added to a solution of3-(2′-t-butoxycarbonylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid (1.0 g, 2.1 mmol; prepared as described in Preparation 3) in DMF(15 mL). The mixture was stirred at room temperature for 16 hours,diluted with saturated aqueous NaCl (100 mL), then extracted with EtOAc(200 mL). The organic layer was evaporated to dryness to yield crudeIntermediate (10a). MS m/z: [M+H⁺] calcd for C₃₀H₃₁N₅O₃, 510.2. found510.6.

4′-(6-Amino-4-methyl-2-propylbenzoimidazol-1-ylmethyl)biphenyl-2-carboxylicacid t-butyl ester (10b): Crude intermediate (10a) was suspended intoluene (300 mL), and heated at 80° C. overnight. The reactant wasconcentrated in vacuo, dissolved in 20% aqueous THF (100 mL), andconcentrated again in vacuo to yield Intermediate (10b) as an oil. MSm/z: [M+H⁺] calcd for C₂₉H₃₃N₃O₂, 456.2. found 456.2.

Intermediate (10b) was suspended in concentrated HCl and heated at 100°C. for 3 hours. The solution was concentrated and the residue purifiedby preparative HPLC to yield the title compound. MS m/z: [M+H⁺] calcdfor C₂₅H₂₅N₃O₂, 400.2. found 400.4.

Example 44′-[6-((S)-2-Acetylsulfanyl-4-methylpentanoylamino)-4-methyl-2-propylbenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicAcid (4a; R^(5a)═—C(O)CH₃) and4′-[6-((S)-2-Mercapto-4-methylpentanoylamino)-4-methyl-2-propylbenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicAcid (4b; R^(5a)═H)

(S)-2-Acetylsulfanyl-4-methylpentanoic acid (15.2 mg, 0.80 mmol;prepared as described in Preparation 9) was dissolved into DMF (1.0 mL).HATU (30.4 mg, 80 μmol) was added, followed by DIPEA (14 μL, 80 μmol)and the solution was stirred for 15 minutes.4′-(6-Amino-4-methyl-2-propylbenzoimidazol-1-ylmethyl)biphenyl-2-carboxylicacid (32 mg, 80 μmol; prepared as described in Preparation 10) in DMF(0.5 mL) and DIPEA (28 μL, 160 μmol) was added to this solution and themixture was shaken at room temperature for 2 hours to give Compound(4a). The mixture was concentrated under reduced pressure and theresidue was dissolved in MeOH (1 mL). The mixture was placed under anatmosphere of nitrogen and a solution of 3N NaOH (0.75 mL) was added andthe mixture was stirred for 2 hours. The solution was acidified with0.50 mL 6N HCl and concentrated under reduced pressure. The recoveredresidue was purified by preparative HPLC to yield Compound (4b) (7.4mg). MS m/z: [M+H⁺] calcd for C₃₁H₃₅N₃O₃S, 530.24. found 530.2.

Example 5

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds5-1 to 5-31, having the following formula, were also prepared:

Ex. R¹ R⁵ R⁶ 5-1 tetrazol-5-yl —CH₂SH —CH₂CH(CH₃)₂ 5-2 —COOH —SH—(CH₂)₂CH₃ 5-3 —COOH —SH —CH₂CH(CH₃)₂ 5-4 —C(O)OC(CH₃)₃ —SC(O)CH₃—(CH₂)₂CH₃ 5-5 —C(O)OC(CH₃)₃ —SC(O)CH₃ —CH₂CH(CH₃)₂ 5-6 tetrazol-5-yl—CH₂SH —CH(CH₃)CH₂CH₃ 5-7 tetrazol-5-yl —CH₂SH —CH₂-naphthalen-1-yl 5-8—COOH —CH₂SH —(CH₂)₃CH₃ 5-9 —COOH —CH₂SH —(CH₂)₂CH(CH₃)₂ 5-10 —COOH—CH₂SH —CH(CH₃)CH₂CH₃ 5-11 —COOH —CH₂SH —CH₂-cyclopentyl 5-12 —COOH—CH₂SH —CH₂-cyclohexyl 5-13 —COOH —CH₂SH —CH₂-naphthalen-1-yl 5-14 —COOH—CH₂SH —(CH₂)₂CH(CH₃)₂ 5-15 —COOH —CH₂SH benzyl 5-16 —COOH —CH₂SH—CH₂-cyclopropyl 5-17 —COOH —CH₂SH —CH(CH₃)₂ 5-18 —COOH —CH₂SH —CH(CH₃)₂5-19 —COOH —SH —(CH₂)₂CH₃ 5-20 —COOH —SH —(CH₂)₂CH₃ 5-21 —COOH —SH—CH₂C(CH₃)₃ 5-22 —COOH —CH₂SH —CH₂CH(CH₃)₂ 5-23 —COOH —SH —CH₂C(CH₃)₃5-24 —COOH —SH —CH₂CH(CH₃)₂ 5-25 —COOH —SH —CH₂CH(CH₃)₂ 5-26 —COOH—CH₂SH —CH₂CH(CH₃)₂ 5-27 tetrazol-5-yl —SH —CH₂CH(CH₃)₂ 5-28tetrazol-5-yl —SH —CH₂C(CH₃)₃ 5-29 tetrazol-5-yl —CH₂SH —CH₂CH(CH₃)₂5-30 tetrazol-5-yl —SH —CH₂CH(CH₃)₂ 5-31 tetrazol-5-yl —CH₂SH—CH₂CH(CH₃)₂(5-1) 2-mercaptomethyl-4-methylpentanoic acid{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazol-5-ylmethyl}amide.MS m/z: [M+H⁺] calcd for C₃₃H₃₉N₇OS, 582.29. found 582.4.(5-2)4′-{6-[(2-mercaptopentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₅N₃O₃S, 530.24. found 530.4.(5-3)4′-{6-[(2-mercapto-4-methylpentanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₇N₃O₃S, 544.26. found 544.4.(5-4)4′-{6-[(2-acetylsulfanylpentanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid t-butyl ester. MS m/z: [M+H⁺] calcd for C₃₇H₄₅N₃O₄S, 628.31. found628.4.(5-5)4′-{6-[(2-acetylsulfanyl-4-methylpentanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid t-butyl ester. MS m/z: [M+H⁺] calcd for C₃₈H₄₇N₃O₄S, 642.33. found642.4.(5-6) 2-mercaptomethyl-3-methylpentanoic acid{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazol-5-ylmethyl}amide.MS m/z: [M+H⁺] calcd for C₃₃H₃₉N₇OS, 582.29. found 582.4.(5-7)2-mercaptomethyl-N-{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazol-5-ylmethy}-3-naphthalen-1-ylpropionamide.MS m/z: [M+H⁺] calcd for C₄₀H₃₉N₇OS, 666.29. found 666.4.(5-8)4′-{6-[(2-mercaptomethyl-hexanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₃H₃₉N₃O₃S, 558.27. found 558.2.(5-9)4′-{6-[(2-mercaptomethyl-5-methyl-hexanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₄H₄₁N₃O₃S, 572.29. found 572.2.(5-10)4′-{6-[(2-mercaptomethyl-3-methylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₃H₃₉N₃O₃S, 558.27. found 558.2.(5-11)4′-{6-[(3-cyclopentyl-2-mercaptomethyl-propionylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₄₁N₃O₃S, 584.29. found 584.2.(5-12)4′-{6-[(3-cyclohexyl-2-mercaptomethyl-propionylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₆H₄₃N₃O₃S, 598.30. found 598.4.(5-13)4′-{6-[(2-mercaptomethyl-3-naphthalen-1-yl-propionylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₀H₃₉N₃O₃S, 642.27. found 642.2.(5-14)4′-{6-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₃H₃₉N₃O₃S, 558.27. found 558.2.(5-15)4′-{6-[(2-mercaptomethyl-3-phenylpropionylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₆H₃₇N₃O₃S, 592.26. found 592.2.(5-16)4′-{6-[(3-cyclopropyl-2-mercaptomethyl-propionylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₃H₃₇N₃O₃S, 556.26. found 556.2.(5-17)4′-{6-[((R)-2-mercaptomethyl-3-methyl-butyrylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₇N₃O₃S, 544.26. found 544.2.(5-18)4′-{6-[((S)-2-mercaptomethyl-3-methyl-butyrylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₇N₃O₃S, 544.26. found 544.2.(5-19)4′-{6-[((S)-2-mercaptopentanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₅N₃O₃S, 530.24. found 530.2.(5-20)4′-{6-[((R)-2-mercaptopentanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₅N₃O₃S, 530.24. found 530.2.(5-21)4′-{6-[((S)-2-mercapto-4,4-dimethylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₃H₃₉N₃O₃S, 558.27. found 558.2.(5-22)4′-{6-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₃H₃₉N₃O₃S, 558.27. found 558.2.(5-23)4′-{6-[((R)-2-mercapto-4,4-dimethylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₃H₃₉N₃O₃S, 558.27. found 558.2.(5-24)4′-{6-[((R)-2-mercapto-4-methylpentanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₇N₃O₃S, 544.26. found 544.2.(5-25)4′-{6-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₇N₃O₃S, 544.26. found 544.2.(5-26)4′-{6-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₃H₃₉N₃O₃S, 558.27. found 558.2.(5-27) (S)-2-mercapto-4-methylpentanoic acid{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazol-5-ylmethyl}amide.MS m/z: [M+H⁺] calcd for C₃₂H₃₇N₇OS, 568.28. found 568.2.(5-28) (S)-2-mercapto-4,4-dimethylpentanoic acid{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazol-5-ylmethyl}aamide.MS m/z: [M+H⁺] calcd for C₃₃H₃₉N₇OS, 582.29. found 582.2.(5-29) (S)-2-mercaptomethyl-4-methylpentanoic acid{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazol-5-ylmethyl}amide.MS m/z: [M+H⁺] calcd for C₃₃H₃₉N₇OS, 582.29. found 582.2.(5-30) (R)-2-mercapto-4-methylpentanoic acid{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazol-5-ylmethyl}amide.MS m/z: [M+H⁺] calcd for C₃₂H₃₇N₇OS, 568.28. found 568.2.(5-31) (R)-2-mercaptomethyl-4-methylpentanoic acid{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazol-5-ylmethyl}amide.MS m/z: [M+H⁺] calcd for C₃₃H₃₉N₇OS, 582.29. found 582.4.

Example 6

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds6-1 to 6-21, having the following formula, were also prepared:

Ex. R¹ R⁵ R⁶ 6-1 —COOH —SH —CH₂CH(CH₃)₂ 6-2 —COOH —CH₂SH —CH₂CH(CH₃)₂6-3 —COOH —CH₂SH benzyl 6-4 —COOH —SH —(CH₂)₂CH₃ 6-5 —COOH —CH₂SH—CH(CH₃)₂ 6-6 —COOH —CH₂SH —CH(CH₃)₂ 6-7 —COOH —CH₂SH —CH₂-cyclopropyl6-8 —COOH —SH —(CH₂)₂CH₃ 6-9 —COOH —CH₂SH —CH₂CH(CH₃)₂ 6-10tetrazol-5-yl —CH₂SH benzyl 6-11 tetrazol-5-yl —CH₂SH —(CH₂)₂CH₃ 6-12tetrazol-5-yl —CH₂SH —CH(CH₃)₂ 6-13 tetrazol-5-yl —SH —CH₂CH(CH₃)₂ 6-14tetrazol-5-yl —SH benzyl 6-15 tetrazol-5-yl —SH —CH₂-cyclopropyl 6-16tetrazol-5-yl —CH₂SH —CH₂-cyclopropyl 6-17 tetrazol-5-yl —CH₂SH—CH₂CH(CH₃)₂ 6-18 tetrazol-5-yl —SH —(CH₂)₂CH₃ 6-19 tetrazol-5-yl —CH₂SH—CH(CH₃)₂ 6-20 tetrazol-5-yl —SH —CH₂CH(CH₃)₂ 6-21 tetrazol-5-yl —SHbenzyl(6-1)4′-[6-((R)-2-mercapto-4-methylpentanoylamino)-4-methyl-2-propyl-benzoimidazol-1-ylmethylbiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₅N₃O₃S, 530.24. found 530.2.(6-2)4′-[6-((S)-2-mercaptomethyl-4-methylpentanoylamino)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₇N₃O₃S, 544.26. found 544.2.(6-3)4′-[6-((S)-2-benzyl-3-mercaptopropionylamino)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₅N₃O₃S, 578.24. found 578.4.(6-4)4′-[6-((S)-2-mercaptopentanoylamino)-4-methyl-2-propylbenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₃N₃O₃S, 516.22; found 516.4.(6-5)4′-[6-((R)-2-mercaptomethyl-3-methylbutyrylamino)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₅N₃O₃S, 530.24. found 530.4.(6-6)4′-[6-((S)-2-mercaptomethyl-3-methylbutyrylamino)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₅N₃O₃S, 530.24. found 530.4.(6-7)4′-[6-((R)-2-cyclopropylmethyl-3-mercaptopropionylamino)-4-methyl-2-propylbenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₅N₃O₃S, 542.24. found 542.6.(6-8)4′-[6-((R)-2-mercaptopentanoylamino)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₄₁N₃O₃S, 548.29; found 548.2.(6-9)4′-[6-((R)-2-mercaptomethyl-4-methylpentanoylamino)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₇N₃O₃S, 544.26. found 544.6.(6-10)(S)-2-benzyl-3-mercapto-N-{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazol-5-yl}propionamide.MS m/z: [M+H⁺] calcd for C₃₅H₃₅N₇OS, 602.26. found 602.6.(6-11) (S)-2-mercaptomethyl-4-methyl-pentanoic acid{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazol-5-yl}aamide.MS m/z: [M+H⁺] calcd for C₃₂H₃₇N₇OS, 568.28. found 568.2.(6-12)(R)-2-mercaptomethyl-3-methyl-N-{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazol-5-yl}butyramide.MS m/z: [M+H⁺] calcd for C₃₁H₃₅N₇OS, 554.26. found 554.2.(6-13) (S)-2-mercapto-4-methylpentanoic acid{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazol-5-yl}amide.MS m/z: [M+H⁺] calcd for C₃₁H₃₅N₇OS, 554.26. found 554.2.(6-14)(S)-2-mercapto-N-{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazol-5-yl}-3-phenylpropionamide.MS m/z: [M+H⁺] calcd for C₃₄H₃₃N₇OS, 588.25. found 588.2.(6-15)(S)-3-cyclopropyl-2-mercapto-N-{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazol-5-yl}propionamide.MS m/z: [M+H⁺] calcd for C₃₁H₃₃N₇OS, 552.25. found 552.2.(6-16)(R)-2-cyclopropylmethyl-3-mercapto-N-{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazol-5-yl}propionamide.MS m/z: [M+H⁺] calcd for C₃₂H₃₅N₇OS, 566.26. found 566.2.(6-17) (R)-2-mercaptomethyl-4-methylpentanoic acid{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazol-5-yl}amide.MS m/z: [M+H⁺] calcd for C₃₂H₃₇N₇OS, 568.28. found 568.2.(6-18) (S)-2-mercapto-pentanoic acid{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazol-5-yl}amide.MS m/z: [M+H⁺] calcd for C₃₀H₃₃N₇OS, 540.25. found 540.2.(6-19)(S)-2-mercaptomethyl-3-methyl-N-{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazol-5-yl}butyramide.MS m/z: [M+H⁺] calcd for C₃₁H₃₅N₇OS, 554.26. found 554.2.(6-20) (R)-2-mercapto-4-methylpentanoic acid{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazol-5-yl}amide.MS m/z: [M+H⁺] calcd for C₃₁H₃₅N₇OS, 554.26. found 554.2.(6-21)(R)-2-mercapto-N-{7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazol-5-yl}-3-phenylpropionamide.MS m/z: [M+H⁺] calcd for C₃₄H₃₃N₇OS, 588.25. found 588.2.

Example 7

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds7-1 to 7-138, having the following formula, were also prepared:

Ex. R¹ R⁵ R⁶ 7-1 tetrazol-5-yl —CH₂—C(O)N(OH)H benzyl 7-2 tetrazol-5-yl—CH₂SC(O)CH₃ benzyl 7-3 tetrazol-5-yl —CH₂SH benzyl 7-4 —COOH—CH₂SC(O)CH₃ benzyl 7-5 tetrazol-5-yl —CH₂N(OH)C(O)H benzyl 7-6tetrazol-5-yl —CH₂N(OH)C(O)CH₃ benzyl 7-7 —COOH —CH₂N(OH)C(O)H benzyl7-8 tetrazol-5-yl —CH₂SH —CH₂CH(CH₃)₂ 7-9 tetrazol-5-yl —CH₂SH—CH₂CH(CH₃)₂ 7-10 —C(O)OC(CH₃)₃ —CH₂C(O)N(OH)H benzyl 7-11 —COOH —CH₂SH—CH₂CH(CH₃)₂ 7-12 —COOH —CH₂N(OH)C(O)H —CH₂CH(CH₃)₂ 7-13 tetrazol-5-yl—CH₂N(OH)C(O)H —CH₂CH(CH₃)₂ 7-14 —C(O)OCH₃ —CH₂SH benzyl 7-15 —COOH—CH₂SC(O)-phenyl benzyl 7-16 —COOH —CH₂SC(O)—CH₂CH₃ benzyl 7-17 —COOH—CH₂—SC(O)— benzyl CH₂CH(CH₃)₂ 7-18 —COOH —CH₂SC(O)—CH(CH₃)₂ benzyl 7-19—COOH —CH₂—SC(O)—CH₂- benzyl cyclopentyl 7-20 —COOH —CH₂SC(O)-cyclohexylbenzyl 7-21 —COOH —CH₂SC(O)-cyclopentyl benzyl 7-22 —COOH—CH₂SC(O)—C(CH₃)₃ benzyl 7-23 —C(O)OCH₂CH₃ —CH₂SH benzyl 7-24—C(O)O—(CH₂)₂CH₃ —CH₂SH benzyl 7-25 —C(O)O— —CH₂SH benzyl CH₂CH(CH₃)₂7-26 —C(O)O—(CH₂)₃CH₃ —CH₂SH benzyl 7-27 —C(O)O-3- —CH₂SH benzylchlorobenzyl 7-28 —C(O)O-4- —CH₂SH benzyl methylbenzyl 7-29 —C(O)O-2,6-—CH₂SH benzyl difluorobenzyl 7-30 —C(O)O-3- —CH₂SH benzyl methoxybenzyl7-31 —C(O)O-benzyl —CH₂SH benzyl 7-32 —C(O)O-3- —CH₂SH benzylfluorobenzyl 7-33 —C(O)O-4- —CH₂SH benzyl chlorobenzyl 7-34—C(O)O—CH(CH₃)— —CH₂SH benzyl OC(O)O-cyclohexyl 7-35 —C(O)O—CH(CH₃)——CH₂SH benzyl OC(O)O—CH(CH₃)₂ 7-36 —COOH —CH₂—SC(O)OCH₂CH₃ benzyl 7-37—C(O)O—CH(CH₃)— —CH₂SH benzyl OC(O)O—CH₂CH₃ 7-38

—CH₂SH benzyl 7-39 —COOH —CH₂— benzyl SC(O)CH(NH₂)CH(CH₃)₂ 7-40 —COOH—CH₂SC(O)-2-pyrrolidine benzyl 7-41 —COOH —CH₂SH 4-fluorobenzyl 7-42—COOH —CH₂SH 4-chlorobenzyl 7-43 —COOH —CH₂SH 3-fluorobenzyl 7-44 —COOH—CH₂SH 4-methylbenzyl 7-45 —COOH —CH₂SH 4-bromobenzyl 7-46 —COOH —CH₂SH—CH₂-thiophen-2-yl 7-47 —COOH —CH₂SH —CH₂-cyclohexyl 7-48 —COOH —CH₂SH2-fluorobenzyl 7-49 —COOH —CH₂SC(O)-2-pyridine benzyl 7-50 —COOH—CH₂SC(O)-4-pyridine benzyl 7-51 —COOH —CH₂SC(O)-3-pyridine benzyl 7-52—COOH —CH₂SC(O)(CH₂)₂- benzyl morpholin-4-yl 7-53 —COOH—CH₂SC(O)(CH₂)₂-4- benzyl methylpiperazin-1-yl 7-54 —COOH —CH₂SC(O)CH₂-benzyl morpholin-4-yl 7-55 —C(C)O(CH₂)₃- —CH₂SH benzyl morpholin-4-yl7-56 —COOH —CH₂SH 3-chlorobenzyl 7-57 —COOH —CH₂SH 3,5-difluorobenzyl7-58 —COOH —CH₂SH 2,4-dichlorobenzyl 7-59 —COOH —CH₂SH 2-chlorobenzyl7-60 —COOH —CH₂SH 2-trifluoro- methylbenzyl 7-61 —C(O)C—(CH₂)₂CH₃ —CH₂SH—CH₂CH(CH₃)₂ 7-62 —COOH —CH₂SC(O)-2pyridine —CH₂CH(CH₃)₂ 7-63 —COOH—CH₂SC(O)-4-pyridine —CH₂CH(CH₃)₂ 7-64 —COOH —CH₂SC(O)-3-pyridine—CH₂CH(CH₃)₂ 7-65 —COOH —CH₂SC(O)(CH₂)₂- —CH₂CH(CH₃)₂ morpholin-4-yl7-66 —COOH —CH₂SC(O)(CH₂)₂-4- —CH₂CH(CH₃)₂ methylpiperazin-1-yl 7-67—COOH —CH₂SC(O)(CH₂)₃- —CH₂CH(CH₃)₂ morpholin-4-yl 7-68 —COOH—CH₂SC(O)CH₂- —CH₂CH(CH₃)₂ morpholin-4-yl 7-69 —COOH —CH₂SC(O)CH₂——CH₂CH(CH₃)₂ OC(O)CH₃ 7-70 —COOH —CH₂SC(O)CH₃ —CH₂CH(CH₃)₂ 7-71 —COOH—CH₂SC(O)-benzyl —CH₂CH(CH₃)₂ 7-72 —COOH —CH₂SC(O)CH₂CH₃ —CH₂CH(CH₃)₂7-73 —COOH —CH₂SC(O)(CH₂)₂CH₃ —CH₂CH(CH₃)₂ 7-74 —COOH—CH₂SC(O)-cyclopentyl —CH₂CH(CH₃)₂ 7-75 —COOH —CH₂SC(O)CH₂- —CH₂CH(CH₃)₂cyclopentyl 7-76 —COOH —CH₂SC(O)-cyclohexyl —CH₂CH(CH₃)₂ 7-77 —COOH—CH₂SC(O)C(CH₃)₃ —CH₂CH(CH₃)₂ 7-78 —COOH —CH₂SC(O)CH(NH₂)- benzyl benzyl7-79 —COOH —CH₂SC(O)CH(NH₂)— benzyl CH(CH₃)CH₂CH₃ 7-80 —COOH—CH₂SC(O)CH(NH₂)— benzyl CH₂CH(CH₃)₂ 7-81 —COOH —CH₂SC(O)CH(NH₂)— benzyl(CH₂)₂SCH₃ 7-82 —COOH —CH₂SC(O)CH(NH₂)— benzyl CH(OH)(CH₃) 7-83 —COOH—CH₂SC(O)CH(NH₂)-4- benzyl hydroxybenzyl 7-84 —COOH —CH₂SC(O)CH(NH₂)—benzyl C(CH₃)₃ 7-85 —COOH —CH₂SC(O)CH(NH₂)— benzyl CH₂CH₃ 7-86 —COOH—CH₂SC(O)CH(NH₂)— benzyl (CH₂)₂CH₃ 7-87 —COOH —CH₂SC(O)CH(NH₂)— benzyl(CH₂)₃CH₃ 7-88 —COOH —CH₂SC(O)CH(NH₂)— benzyl CH₂-cyclohexyl 7-89 —COOH—CH₂SC(O)CH(NH₂)— benzyl CH₂-cyclobutyl 7-90 —COOH

benzyl 7-91 —COOH

benzyl 7-92 —COOH

benzyl 7-93 —COOH —CH₂SC(O)-2- benzyl aminophenyl 7-94 —COOH—CH₂SC(O)-3- benzyl aminophenyl 7-95 —COOH —CH₂SC(O)CH(NH₂)-—CH₂CH(CH₃)₂ benzyl 7-96 —COOH —CH₂SC(O)CH(NH₂)- —CH₂CH(CH₃)₂CH(CH₃)CH₂CH₃ 7-97 —COOH —CH₂SC(O)CH(NH₂)- —CH₂CH(CH₃)₂ CH₂CH(CH₃)₂ 7-98—COOH —CH₂SC(O)CH(NH₂)- —CH₂CH(CH₃)₂ (CH₂)₂SCH₃ 7-99 —COOH—CH₂SC(O)CH(NH₂)-4- —CH₂CH(CH₃)₂ hydroxybenzyl 7-100 —COOH—CH₂SC(O)CH(NH₂)— —CH₂CH(CH₃)₂ C(CH₃)₃ 7-101 —COOH —CH₂SC(O)CH(NH₂)——CH₂CH(CH₃)₂ CH₂CH₃ 7-102 —COOH —CH₂SC(O)CH(NH₂)— —CH₂CH(CH₃)₂CH₂-cyclohexyl 7-103 —COOH —CH₂SC(O)CH(NH₂)— —CH₂CH(CH₃)₂ CH₂-cyclobutyl7-104 —COOH

—CH₂CH(CH₃)₂ 7-105 —COOH

—CH₂CH(CH₃)₂ 7-106 —COOH

—CH₂CH(CH₃)₂ 7-107 —COOH —CH₂SC(O)- —CH₂CH(CH₃)₂ tetrahydrofuran-2-yl7-108 —COOH —CH₂SC(O)-2- —CH₂CH(CH₃)₂ aminophenyl 7-109 —COOH—CH₂SC(O)-3- —CH₂CH(CH₃)₂ aminophenyl 7-110 —COOH —CH₂SC(O)-4-—CH₂CH(CH₃)₂ aminophenyl 7-111 —COOH —CH₂SC(O)CH(NH₂)— —CH₂CH(CH₃)₂CH(CH₃)₂ 7-112 —COOH —CH₂SC(O)-2-pyrrolidine —CH₂CH(CH₃)₂ 7-113 —COOH—CH₂SH 2-fluorobenzyl 7-114 —COOH —CH₂SC(O)CH₂N(CH₃)₂ benzyl 7-115 —COOH—CH₂SC(O)— benzyl (CH₂)₂N(CH₃)₂ 7-116 —COOH —CH₂SC(O)— benzyl(CH₂)₃N(CH₃)₂ 7-117 —COOH —CH₂SC(O)—CH₂-2- benzyl methylpiperidin-1-yl7-118 —COOH —CH₂SC(O)—CH₂-3- benzyl methylpiperidin-2-yl 7-119 —COOH—CH₂SC(O)— —CH₂CH(CH₃)₂ (CH₂)₃N(CH₃)₂ 7-120 —COOH —CH₂SC(O)—CH₂-2-—CH₂CH(CH₃)₂ piperidin-1-yl 7-121 —COOH —CH₂SC(O)(CH₂)₂COOH benzyl 7-122—COOH —CH₂SC(O)-4- benzyl carboxyphenyl 7-123 —COOH —CH₂SC(O)— benzylCH(NH₂)(CH₂)₂COOH 7-124 —COOH —CH₂SC(O)— benzyl CH₂CH(NH₂)COOH 7-125—COOH —CH₂SC(O)-3- benzyl carboxyphenyl 7-126 —COOH —CH₂SC(O)(CH₂)₂COOH—CH₂CH(CH₃)₂ 7-127 —COOH —CH₂SC(O)-3- —CH₂CH(CH₃)₂ carboxyphenyl 7-128—COOH —CH₂SC(O)-4- —CH₂CH(CH₃)₂ carboxyphenyl 7-129 —COOH—CH₂SC(O)CH(NH₂)— —CH₂CH(CH₃)₂ (CH₂)₂COOH 7-130 —COOH —CH₂SC(O)——CH₂CH(CH₃)₂ CH₂CH(NH₂)—COOH 7-131 —COOH —CH₂—N(OH)C(O)H 3-fluorobenzyl7-132 —COOH —CH₂—N(OH)C(O)H 2-fluorobenzyl 7-133 —COOH —CH₂—N(OH)C(O)H4-methylbenzyl 7-134 —COOH —CH₂SC(O)—CH(NH₂)— benzyl CH₂COOH 7-135 —COOH—CH₂SC(O)— benzyl (CH₂)₂CH(NH₂)—COOH 7-136 —COOH —CH₂SC(O)— —CH₂CH(CH₃)₂(CH₂)₂CH(NH₂)—COOH 7-137 —COOH —CH₂SC(O)—CH(NH₂)— —CH₂CH(CH₃)₂ CH₂COOH7-138 —COOH —CH₂SC(O)CH₂N(CH₃)₂ —CH₂CH(CH₃)₂(7-1)7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazole-5-carboxylicacid ((R)-1-benzyl-2-hydroxycarbamoylethyl)amide. MS m/z: [M+H⁺] calcdfor C₃₆H₃₆N₈O₃, 629.29. found 629.6.(7-2) thioacetic acidS—[(R)-2-({7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazole-5-carbonyl}amino)-3-phenylpropyl]ester.MS m/z: [M+H⁺] calcd for C₃₇H₃₇N₇O₂S, 644.27. found 644.3.(7-3)7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazole-5-carboxylicacid ((R)-1-benzyl-2-mercaptoethyl)amide. MS m/z: [M+H⁺] calcd forC₃₅H₃₅N₇OS, 602.26. found 602.6.(7-4)4′-[6-((R)-2-acetylsulfanyl-1-benzylethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₇H₃₇N₃O₄S, 620.25. found 620.8.(7-5)7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazole-5-carboxylicacid [(R)-1-benzyl-2-(formylhydroxyamino)ethyl]amide. MS m/z: [M+H⁺]calcd for C₃₆H₃₆N₈O₃, 629.29. found 629.6.(7-6)7-methyl-2-propyl-3-[21′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazole-5-carboxylicacid [(R)-2-(acetylhydroxyamino)-1-benzylethyl]amide. MS m/z: [M+H⁺]calcd for C₃₇H₃₈N₈O₃, 643.31. found 643.5.(7-7)4′-{6-[(R)-1-benzyl-2-(formylhydroxyamino)ethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₆H₃₆N₄O₅, 605.27. found 605.6.(7-8)7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methyl-butyl)-amide. MS m/z: [M+H⁺] calcdfor C₃₂H₃₇N₇OS, 568.28. found 568.6.(7-9)7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazole-5-carboxylicacid ((S)-1-mercaptomethyl-3-methylbutyl)amide. MS m/z: [M+H⁺] calcd forC₃₂H₃₇N₇OS, 568.28. found 568.6.(7-10)4′-[6-((R)-1-benzyl-2-hydroxycarbamoyl-ethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid t-butyl ester. MS m/z: [M+H⁺] calcd for C₄₀H₄₄N₄O₅, 661.33. found661.4.(7-11)4′-[6-((R)-1-mercaptomethyl-3-methyl-butylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₇N₃O₃S, 544.26. found 544.4.(7-12){(R)-1-[(formylhydroxyamino)methyl]-3-methyl-butylcarbamoyl}-4-methyl-2-propylbenzoimidazol-1-ylmethyl)biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₃H₃₈N₄O₅, 571.28. found 571.6.(7-13)7-methyl-2-propyl-3-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-3H-benzoimidazole-5-carboxylicacid {(R)-1-[(formylhydroxyamino)methyl]-3-methylbutyl}amide. MS m/z:[M+H⁺] calcd for C₃₃H₃₈N₈O₃, 595.31. found 595.5.(7-14)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid methyl ester. MS m/z: [M+H⁺] calcd for C₃₆H₃₇N₃O₃S, 592.26. found592.8.(7-15)4′-[6-((R)-2-benzoylsulfanyl-1-benzylethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₂H₃₉N₃O₄S, 682.27. found 682.2.(7-16)4′-[6-((R)-1-benzyl-2-propionylsulfanyl-ethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₈H₃₉N₃O₄S, 634.27. found 634.2.(7-17)4′-{6-[(R)-1-benzyl-2-(3-methyl-butyrylsulfanyl)ethylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₀H₄₃N₃O₄S, 662.30. found 662.2.(7-18)4′-[6-((R)-1-benzyl-2-isobutyrylsulfanylethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₉H₄₁N₃O₄S, 648.28. found 648.2.(7-19)4′-{6-[(R)-1-benzyl-2-(2-cyclopentylacetylsulfanyl)ethylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₂H₄₅N₃O₄S, 688.31. found 688.2.(7-20)4′-[6-((R)-1-benzyl-2-cyclohexanecarbonylsulfanylethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₂H₄₅N₃O₄S, 688.31. found 688.2.(7-21)4′-[6-((R)-1-benzyl-2-cyclopentanecarbonylsulfanylethyl-carbamoyl)-4-methyl-2-propylbenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₁H₄₃N₃O₄S, 674.30. found 674.2.(7-22)4′-{6-[(R)-1-benzyl-2-(2,2-dimethylpropionylsulfanyl)ethyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₀H₄₃N₃O₄S, 662.30. found 662.2.(7-23)4′-[6-((R)-1-Benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid ethyl ester. MS m/z: [M+H⁺] calcd for C₃₇H₃₉N₃O₃S, 606.27. found606.6.(7-24)4′-[6-((R)-1-Benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid propyl ester. MS m/z: [M+H⁺] calcd for C₃₈H₄₁N₃O₃S, 620.29. found620.2.(7-25)4′-[6-((R)-1-Benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid isobutyl ester. MS m/z: [M+H⁺] calcd for C₃₉H₄₃N₃O₃S, 634.30. found634.2.(7-26)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid butyl ester. MS m/z: [M+H⁺] calcd for C₃₉H₄₃N₃O₃S, 634.30. found634.2.(7-27)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid 3-chlorobenzyl ester. MS m/z: [M+H⁺] calcd for C₄₂H₄₀ClN₃O₃S,702.25. found 702.2.(7-28)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid 4-methylbenzyl ester. MS m/z: [M+H⁺] calcd for C₄₃H₄₃N₃O₃S, 682.30.found 682.2.(7-29)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid 2,6-difluorobenzyl ester. MS m/z: [M+H⁺] calcd for C₄₂H₃₉F₂N₃O₃S,704.27. found 704.2.(7-30)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid 3-methoxybenzyl ester. MS m/z: [M+H⁺] calcd for C₄₃H₄₃N₃O₄S,698.30. found 698.2.(7-31)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid benzyl ester. MS m/z: [M+H⁺] calcd for C₄₂H₄₁N₃O₃S, 668.29. found668.2.(7-32)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid 3-fluorobenzyl ester. MS m/z: [M+H⁺] calcd for C₄₂H₄₀FN₃O₃S,686.28. found 686.2.(7-33)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid 4-chlorobenzyl ester. MS m/z: [M+H⁺] calcd for C₄₂H₄₀ClN₃O₃S,702.25. found 702.4.(7-34)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid 1-cyclohexyloxycarbonyloxyethyl ester. MS m/z: [M+H⁺] calcd forC₄₄H₄₉N₃O₆S, 748.33. found 748.0.(7-35)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid 1-isopropoxycarbonyloxyethyl ester. MS m/z: [M+H⁺] calcd forC₄₁H₄₅N₃O₆S, 708.30. found 708.4.(7-36)4′-[6-((R)-1-benzyl-2-ethoxycarbonylsulfanylethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₈H₃₉N₃O₅S, 650.26. found 650.2.(7-37)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid 1-ethoxycarbonyloxyethyl ester. MS m/z: [M+H⁺] calcd forC₄₀H₄₃N₃O₆S, 694.29. found 694.0.(7-38)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid 3-oxo-1,3-dihydroisobenzofuran-1-yl ester. MS m/z: [M+H⁺] calcd forC₄₃H₃₉N₃O₅S, 710.26. found 710.8.(7-39)4′-{6-[(R)-2-((S)-2-amino-3-methylbutyrylsulfanyl)-1-benzylethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₀H₄₄N₄O₄S, 677.31. found 677.4.(7-40)4′-{6-[(R)-1-benzyl-2-((S)-pyrrolidine-2-carbonylsulfanyl)ethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₀H₄₂N₄O₄S, 675.29. found 675.6.(7-41)4′-{6-[(R)-2-(4-fluorophenyl)-1-mercaptomethylethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₄FN₃O₃S, 596.23. found 596.4.(7-42)4′-{6-[(R)-2-(4-chlorophenyl)-1-mercaptomethylethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₄ClN₃O₃S, 612.20. found 612.3.(7-43)4′-{6-[(R)-2-(3-fluorophenyl)-1-mercaptomethylethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₄FN₃O₃S, 596.23. found 596.4.(7-44)4′-[6-((R)-1-mercaptomethyl-2-p-tolylethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₆H₃₇N₃O₃S, 592.26. found 592.5.(7-45)4′-{6-[(R)-2-(4-bromophenyl)-1-mercaptomethylethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₄BrN₃O₃S, 656.15. found 658.3 (+2isotopic effect due to bromide).(7-46)4′-[6-((R)-2-mercapto-1-thiophen-2-ylmethylethylcarbamoyl)-4-methyl-2-propylbenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₃H₃₃N₃O₃S₂, 584.20. found 584.0.(7-47)4′-[6-((R)-1-cyclohexylmethyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₄₁N₃O₃S, 584.29. found 584.4.(7-48)4′-{6-[(R)-1-(2-fluorobenzyl)-2-mercaptoethylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₄FN₃O₃S, 596.23. found 596.6.(7-49)4′-{6-[(R)-1-benzyl-2-(pyridine-2-carbonylsulfanyl)ethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₁H₃₈N₄O₄S, 683.26. found 683.2.(7-50)4′-{6-[(R)-1-benzyl-2-(pyridine-4-carbonylsulfanyl)ethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₁H₃₈N₄O₄S, 683.26. found 683.2.(7-51)4′-{6-[(R)-1-benzyl-2-(pyridine-3-carbonylsulfanyl)ethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₁H₃₈N₄O₄S, 683.26. found 683.2.(7-52)4′-{6-[(R)-1-benzyl-2-(3-morpholin-4-ylpropionyl-sulfanyl)ethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₂H₄₆N₄O₅S, 719.32. found 719.2.(7-53)4′-(6-{(R)-1-benzyl-2-[3-(4-methylpiperazin-1-yl)propionyl-sulfanyl]ethyl-carbamoyl}-4-methyl-2-propylbenzoimidazol-1-ylmethyl)biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₃H₄₉N₅O₄S, 732.35. found 732.4.(7-54)4′-{6-[(R)-1-benzyl-2-(2-morpholin-4-ylacetylsulfanyl)ethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₁H₄₄N₄O₅S, 705.30. found 705.2.(7-55)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid 3-morpholin-4-yl-propyl ester. MS m/z: [M+H⁺] calcd forC₄₂H₄₈N₄O₄S, 705.34. found 705.8.(7-56)4′-{6-[(R)-1-(3-chlorobenzyl)-2-mercaptoethylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₄ClN₃O₃S, 612.20. found 612.4.(7-57)4′-{6-[(R)-1-(3,5-difluorobenzyl)-2-mercaptoethylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₃F₂N₃O₃S, 614.22. found 614.4.(7-58)4′-{6-[(R)-1-(2,4-dichlorobenzyl)-2-mercaptoethylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₃Cl₂N₃O₃S, 646.16. found 646.4.(7-59)4′-{6-[(R)-1-(2-chlorobenzyl)-2-mercaptoethylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₄ClN₃O₃S, 612.20. found 612.2.(7-60)4′-{6-[(R)-2-mercapto-1-(2-trifluoromethylbenzyl)ethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₆H₃₄F₃N₃O₃S, 646.23. found 646.6.(7-61)4′-[6-((R)-1-mercaptomethyl-3-methylbutylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid propyl ester. MS m/z: [M+H⁺] calcd for C₃₅H₄₃N₃O₃S, 586.30. found586.2.(7-62)4′-{4-methyl-6-[(R)-3-methyl-1-(pyridine-2-carbonylsulfanylmethyl)butyl-carbamoyl]-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₈H₄₀N₄O₄S, 649.28. found 649.2.(7-63)4′-{4-methyl-6-[(R)-3-methyl-1-(pyridine-4-carbonylsulfanylmethyl)butyl-carbamoyl]-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₈H₄₀N₄O₄S, 649.28. found 649.2.(7-64)4′-{4-methyl-6-[(R)-3-methyl-1-(pyridine-3-carbonylsulfanylmethyl)butyl-carbamoyl]-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₈H₄₀N₄O₄S, 649.28. found 649.2.(7-65)4′-{4-methyl-6-[(R)-3-methyl-1-(3-morpholin-4-yl-propionylsulfanylmethyl)-butylcarbamoyl]-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₉H₄₈N₄O₅S, 685.33. found 685.4.(7-66)4′-(4-methyl-6-{(R)-3-methyl-1-[3-(4-methylpiperazin-1-yl)-propionylsulfanyl-methyl]-butylcarbamoyl}-2-propylbenzoimidazol-1-ylmethyl)biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₀H₅₁N₅O₄S, 698.37. found 698.4.(7-67)4′-{4-methyl-6-[(R)-3-methyl-1-(4-morpholin-4-yl-butyrylsulfanylmethyl)-butylcarbamoyl]-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₀H₅₀N₄O₅S, 699.35. found 699.4.(7-68)4′-{4-methyl-6-[(R)-3-methyl-1-(2-morpholin-4-yl-acetylsulfanylmethyl)-butylcarbamoyl]-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₈H₄₆N₄O₅S, 671.32. found 671.2.(7-69)4′-{6-[(R)-1-(2-acetoxy-acetylsulfanylmethyl)-3-methyl-butylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₆H₄₁N₃O₆S, 644.27. found 644.2.(7-70)4′-[6-((R)-1-acetylsulfanylmethyl-3-methylbutylcarbamoyl)-4-methyl-2-propylbenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₄H₃₉N₃O₄S, 586.27. found 586.2.(7-71)4′-[6-((R)-1-benzoylsulfanylmethyl-3-methylbutylcarbamoyl)-4-methyl-2-propylbenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₉H₄₁N₃O₄S, 648.28. found 648.2.(7-72)4′-[4-methyl-6-((R)-3-methyl-1-propionylsulfanylmethylbutylcarbamoyl)-2-propylbenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₄₁N₃O₄S, 600.28. found 600.2.(7-73)4′-[6-((R)-1-butyrylsulfanylmethyl-3-methylbutylcarbamoyl)-4-methyl-2-propylbenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₆H₄₃N₃O₄S, 614.30. found 614.2.(7-74)4′-[6-((R)-1-cyclopentanecarbonylsulfanylmethyl-3-methylbutylcarbamoyl)-4-methyl-2-propylbenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₈H₄₅N₃O₄S, 640.31. found 640.2.(7-75)4′-{6-[(R)-1-(2-cyclopentylacetylsulfanylmethyl)-3-methylbutylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₉H₄₇N₃O₄S, 654.33. found 654.4.(7-76)4′-[6-((R)-1-cyclohexanecarbonylsulfanylmethyl-3-methyl-butylcarbamoyl)-4-methyl-2-propylbenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₉H₄₇N₃O₄S, 654.33. found 654.2.(7-77)4′-{6-[(R)-1-(2,2-dimethyl-propionylsulfanylmethyl)-3-methyl-butyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₇H₄₅N₃O₄S, 628.31. found 628.2.(7-78)4′-{6-[(R)-2-((S)-2-amino-3-phenyl-propionylsulfanyl)-1-benzylethyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₄H₄₄N₄O₄S, 725.31. found 725.2.(7-79)4′-{6-[(R)-2-((S)-2-amino-3-methyl-pentanoylsulfanyl)-1-benzylethyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₁H₄₆N₄O₄S, 691.32. found 691.4.(7-80)4′-{6-[(R)-2-((S)-2-amino-4-methylpentanoylsulfanyl)-1-benzylethyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₁H₄₆N₄O₄S, 691.32. found 691.4.(7-81)4′-{6-[(R)-2-((S)-2-amino-4-methylsulfanylbutyrylsulfanyl)-1-benzylethyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₀H₄₄N₄O₄S₂, 709.28. found 709.2.(7-82)4′-{6-[(R)-2-((S)-2-amino-3-hydroxybutyrylsulfanyl)-1-benzylethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₉H₄₂N₄O₅S, 679.29. found 679.2.(7-83)4′-(6-{(R)-2-[(S)-2-amino-3-(4-hydroxyphenyl)propionylsulfanyl]-1-benzyl-ethylcarbamoyl}-4-methyl-2-propylbenzoimidazol-1-ylmethyl)biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₄H₄₄N₄O₅S, 741.30. found 741.2.(7-84)4′-{6-[(R)-2-((S)-2-amino-3,3-dimethylbutyrylsulfanyl)-1-benzylethyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₁H₄₆N₄O₄S, 691.32. found 691.4.(7-85)4′-{6-[(R)-2-((S)-2-aminobutyrylsulfanyl)-1-benzylethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₉H₄₂N₄O₄S, 663.29. found 663.2.(7-86)4′-{6-[(R)-2-((S)-2-aminopentanoylsulfanyl)-1-benzylethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₀H₄₄N₄O₄S, 677.31. found 677.4.(7-87)4′-{6-[(R)-2-((S)-2-aminohexanoylsulfanyl)-1-benzylethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₁H₄₆N₄O₄S, 691.32. found 691.4.(7-88)4′-{6-[(R)-2-((S)-2-amino-3-cyclohexylpropionylsulfanyl)-1-benzylethyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₄H₅₀N₄O₄S, 731.36. found 731.4.(7-89)4′-{6-[(R)-2-((S)-2-amino-3-cyclobutylpropionylsulfanyl)-1-benzylethyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₂H₄₆N₄O₄S, 703.32. found 703.4.(7-90)4′-{6-[(R)-2-(1-aminocyclobutanecarbonylsulfanyl)-1-benzylethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₀H₄₂N₄O₄S, 675.29. found 675.2.(7-91)4′-{6-[(R)-2-(1-aminocyclopentanecarbonylsulfanyl)-1-benzylethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₁H₄₄N₄O₄S, 689.31. found 689.2.(7-92)4′-{6-[(R)-2-(1-aminocyclohexanecarbonylsulfanyl)-1-benzylethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₂H₄₆N₄O₄S, 703.32. found 703.2.(7-93)4′-{6-[(R)-2-(2-aminobenzoylsulfanyl)-1-benzylethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₂H₄₀N₄O₄S, 697.28. found 697.2.(7-94)4′-{6-[(R)-2-(3-aminobenzoylsulfanyl)-1-benzylethylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₂H₄₀N₄O₄S, 697.28. found 697.2.(7-95)4′-{6-[(R)-1-((S)-2-amino-3-phenylpropionylsulfanylmethyl)-3-methylbutyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₁H₄₆N₄O₄S, 691.32. found 691.4.(7-96)4′-{6-[(R)-1-((S)-2-amino-3-methylpentanoylsulfanylmethyl)-3-methylbutyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₈H₄₈N₄O₄S, 657.34. found 657.4.(7-97)4′-{6-[(R)-1-((S)-2-amino-4-methylpentanoylsulfanylmethyl)-3-methylbutyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₈H₄₈N₄O₄S, 657.34. found 657.4.(7-98)4′-{6-[(R)-1-((S)-2-amino-4-methylsulfanylbutyrylsulfanylmethyl)-3-methyl-butylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₇H₄₆N₄O₄S₂, 675.30. found 675.2.(7-99)4′-(6-{(R)-1-[(S)-2-amino-3-(4-hydroxyphenyl)-propionylsulfanylmethyl]-3-methyl-butylcarbamoyl}-4-methyl-2-propylbenzoimidazol-1-ylmethyl)biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₁H₄₆N₄O₅S, 707.32. found 707.2.(7-100)4′-{6-[(R)-1-((S)-2-amino-3,3-dimethyl-butyrylsulfanylmethyl)-3-methyl-butylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₈H₄₈N₄O₄S, 657.34. found 657.4.(7-101)4′-{6-[(R)-1-((S)-2-aminobutyrylsulfanylmethyl)-3-methyl-butylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₆H₄₄N₄O₄S, 629.31. found 629.2.(7-102)4′-{6-[(R)-1-((S)-2-amino-3-cyclohexylpropionylsulfanylmethyl)-3-methyl-butylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₁H₅₂N₄O₄S, 697.37. found 697.4.(7-103)4′-{6-[(R)-1-((S)-2-amino-3-cyclobutyl-propionylsulfanylmethyl)-3-methyl-butylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₉H₄₈N₄O₄S, 669.34. found 669.4.(7-104)4′-{6-[(R)-1-(1-aminocyclobutanecarbonylsulfanylmethyl)-3-methylbutyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₇H₄₄N₄O₄S, 641.31. found 641.2.(7-105)4′-{6-[(R)-1-(1-aminocyclopentanecarbonylsulfanylmethyl)-3-methylbutyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₈H₄₆N₄O₄S, 655.32. found 655.4.(7-106)4′-{6-[(R)-1-(1-aminocyclohexanecarbonylsulfanylmethyl)-3-methylbutyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₉H₄₈N₄O₄S, 669.34. found 669.4.(7-107)4′-{4-methyl-6-[(R)-3-methyl-1-((S)-tetrahydrofuran-2-carbonylsulfanyl-methyl)-butylcarbamoyl]-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₇H₄₃N₃O₅S, 642.29. found 642.2.(7-108)4′-{6-[(R)-1-(2-aminobenzoylsulfanylmethyl)-3-methyl-butylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₉H₄₂N₄O₄S, 663.29. found 663.2.(7-109)4′-{6-[(R)-1-(3-aminobenzoylsulfanylmethyl)-3-methyl-butylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₉H₄₂N₄O₄S, 663.29. found 663.2.(7-110)4′-{6-[(R)-1-(4-aminobenzoylsulfanylmethyl)-3-methyl-butylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₉H₄₂N₄O₄S, 663.29. found 663.2.(7-111)4′-{6-[(R)-1-((S)-2-amino-3-methylbutyrylsulfanylmethyl)-3-methylbutyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₇H₄₆N₄O₄S, 643.32. found 643.4.(7-112)4′-{4-methyl-6-[(R)-3-methyl-1-((S)-pyrrolidine-2-carbonylsulfanylmethyl)-butylcarbamoyl]-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₇H₄₄N₄O₄S, 641.31. found 641.2.(7-113)2-(5-{6-[(R)-1-(2-fluorobenzyl)-2-mercaptoethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}-pyridin-2-yl)benzoicacid. MS m/z: [M+H⁺] calcd for C₃₄H₃₃FN₄O₃S, 597.23. found 597.6.(7-114)4′-{6-[(R)-1-benzyl-2-(2-dimethylaminoacetylsulfanyl)-ethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₉H₄₂N₄O₄S, 663.29. found 663.2.(7-115)4′-{6-[(R)-1-benzyl-2-(3-dimethylaminopropionylsulfanyl)-ethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₀H₄₄N₄O₄S, 677.31. found 676.2.(7-116)4′-{6-[(R)-1-benzyl-2-(4-dimethylaminobutyrylsulfanyl)-ethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₁H₄₆N₄O₄S, 691.32. found 691.4.(7-117)4′-(6-{(R)-1-benzyl-2-[2-(2-methylpiperidin-1-yl)-acetylsulfanyl]-ethyl-carbamoyl}-4-methyl-2-propylbenzoimidazol-1-ylmethyl)biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₃H₄₈N₄O₄S, 717.34. found 717.4.(7-118)4′-(6-{(R)-1-benzyl-2-[2-(3-methylpiperidin-1-yl)-acetylsulfanyl]-ethyl-carbamoyl}-4-methyl-2-propylbenzoimidazol-1-ylmethyl)biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₃H₄₈N₄O₄S, 717.34. found 717.4.(7-119)4′-{6-[(R)-1-(4-dimethylaminobutyrylsulfanylmethyl)-3-methylbutyl-carbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₈H₄₈N₄O₄S, 657.34. found 657.4.(7-120)4′-{4-methyl-6-[(R)-3-methyl-1-(2-piperidin-1-yl-acetylsulfanylmethyl)-butyl-carbamoyl]-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₉H₄₈N₄O₄S, 669.34. found 669.4.(7-121)4′-{6-[(R)-1-benzyl-2-(3-carboxypropionylsulfanyl)ethylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₉H₃₉N₃O₆S, 678.26. found 678.2.(7-122)4′-{6-[(R)-1-benzyl-2-(4-carboxybenzoylsulfanyl)ethylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₃H₃₉N₃O₆S, 726.26. found 726.2.(7-123)4′-{6-[(R)-2-((S)-2-amino-4-carboxybutyrylsulfanyl)-1-benzyl-ethylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₀H₄₂N₄O₆S, 707.28. found 707.2.(7-124)4′-{6-[(R)-2-((S)-3-amino-3-carboxypropionylsulfanyl)-1-benzylethyl-carbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₉H₄₀N₄O₆S, 693.27. found 693.2.(7-125)4′-{6-[(R)-1-benzyl-2-(3-carboxybenzoylsulfanyl)-ethylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₃H₃₉N₃O₆S, 726.26. found 726.2.(7-126)4′-{6-[(R)-1-(3-carboxypropionylsulfanylmethyl)-3-methylbutylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₆H₄₁N₃O₆S, 644.27. found 644.2.(7-127)4′-{6-[(R)-1-(3-carboxybenzoylsulfanylmethyl)-3-methyl-butylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₀H₄₁N₃O₆S, 692.27. found 692.2.(7-128)4′-{6-[(R)-1-(4-carboxybenzoylsulfanylmethyl)-3-methyl-butylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₀H₄₁N₃O₆S, 692.27. found 692.2.(7-129)4′-{6-[(R)-1-((S)-2-amino-4-carboxybutyrylsulfanylmethyl)-3-methylbutyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₇H₄₄N₄O₆S, 673.30. found 673.2.(7-130)4′-{6-[(R)-1-((S)-3-amino-3-carboxypropionylsulfanylmethyl)-3-methylbutyl-carbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₆H₄₂N₄O₆S, 659.28. found 659.2.(7-131)4′-{6-[(R)-1-(3-fluorobenzyl)-2-(formylhydroxyamino)ethylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₆H₃₅FN₄O₅, 623.26. found 623.2.(7-132)4′-{6-[(R)-1-(2-fluorobenzyl)-2-(formylhydroxyamino)ethylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₆H₃₅FN₄O₅, 623.26. found 623.2.(7-133)4′-{6-[(R)-2-(formylhydroxyamino)-1-(4-methylbenzyl)ethylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₇H₃₉N₄O₅, 619.28. found 619.2.(7-134)4′-{6-[(R)-2-((S)-2-amino-3-carboxypropionylsulfanyl)-1-benzylethyl-carbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₉H₄₀N₄O₆S, 693.27. found 693.2.(7-135)4′-{6-[(R)-2-((S)-4-amino-4-carboxybutyrylsulfanyl)-1-benzylethylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₄₀H₄₂N₄O₆S, 707.28. found 707.6.(7-136)4′-{6-[(R)-1-((S)-4-amino-4-carboxybutyrylsulfanylmethyl)-3-methylbutyl-carbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₇H₄₄N₄O₆S, 673.30. found 673.6.(7-137)4′-{6-[(R)-1-((R)-2-amino-3-carboxypropionylsulfanylmethyl)-3-methylbutyl-carbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₆H₄₂N₄O₆S, 659.28. found 659.6.(7-138)4′-{6-[(R)-1-(2-dimethylaminoacetylsulfanylmethyl)-3-methylbutylcarbamoyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₆H₄₄N₄O₄S, 629.31. found 629.8.

Example 8

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds8-1 to 8-50, having the following formula, were also prepared:

Ex. R R⁵ R⁶ 8-1 H —CH₂—SH —CH₂CH(CH₃)₂ 8-2 H —CH₂—SH benzyl 8-3 H—CH₂—SH —CH₂-cyclopropyl 8-4 H —SH benzyl 8-5 H —C(O)N(OH)H benzyl 8-6 H—CH₂—SH —(CH₂)₃CH₃ 8-7 H —SH —(CH₂)₂CH₃ 8-8 H —SH —(CH₂)₂CH₃ 8-9 H—CH₂—SH —CH(CH₃)₂ 8-10 Br —CH₂—SH —CH₂-cyclohexyl 8-11 Br —SH—CH₂CH(CH₃)₂ 8-12 Br —SH —CH₂C(CH₃)₃ 8-13 Br —SH —(CH₂)₂CF₃ 8-14 Br—CH₂—SH —CH₂CH(CH₃)₂ 8-15 Br —CH₂—SH —CH(CH₃)₂ 8-16 Br —SH —(CH₂)₂CH₃8-17 Br —SH benzyl 8-18 Br —CH₂—SH benzyl 8-19 Br —CH₂—SH —(CH₂)₂CH₃8-20 Br —CH₂—SH —(CH₂)₂CH(CH₃)₂ 8-21 Br —SH —CH₂CH(CH₃)₂ 8-22 Br —SH—CH₂C(CH₃)₃ 8-23 Br —SH —(CH₂)₂CH₃ 8-24 Br —CH₂—SH —CH₂CH(CH₃)₂ 8-25 H—SH —CH₂CH(CH₃)₂ 8-26 H —SH —CH₂C(CH₃)₃ 8-27 H —SH —(CH₂)₂CF₃ 8-28 H —SH—(CH₂)₃CF₃ 8-29 H —SH —CH₂CH(CH₃)₂ 8-30 H —CH₂—SH —CH₂CH(CH₃)₂ 8-31 H—CH₂—SH —CH₂CH(CH₃)₂ 8-32 H —SH —CH₂C(CH₃)₃ 8-33 Br —CH₂—SH —CH₂CH(CH₃)₂8-34 F —CH₂—SH —CH₂CH(CH₃)₂ 8-35 F —SH —CH₂C(CH₃)₃ 8-36 F —SH —(CH₂)₂CF₃8-37 F —SH —(CH₂)₃CF₃ 8-38 F —SH —(CH₂)₂CH₃ 8-39 F —CH₂—SH —(CH₂)₃CH₃8-40 F —CH₂—SH —(CH₂)₂CH(CH₃)₂ 8-41 F —CH₂—SH —CH(CH₃)CH₂CH₃ 8-42 F—CH₂—SH —CH₂-cyclopentyl 8-43 F —CH₂—SH —CH₂-cyclohexyl 8-44 F —CH₂—SHbenzyl 8-45 F —SH benzyl 8-46 F —CH₂—SH —CH₂CH(CH₃)₂ 8-47 F —CH₂—SH—CH(CH₃)₂ 8-48 F —SH —(CH₂)₂CH₃ 8-49 F —SH —CH₂C(CH₃)₃ 8-50 F —SH—CH₂CH(CH₃)₂(8-1)4-{6-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₅N₃O₃S, 482.24. found 482.2.(8-2)4-{6-[(2-mercaptomethyl-3-phenylpropionylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₃N₃O₃S, 516.22. found 516.2.(8-3)4-{6-[(3-cyclopropyl-2-mercaptomethyl-propionylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₃N₃O₃S, 480.22. found 480.2.(8-4)4-{6-[((S)-2-mercapto-3-phenylpropionylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₁N₃O₃S, 502.21. found 502.2.(8-5)4-{6-[(2-hydroxycarbamoyl-3-phenylpropionylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₂N₄O₅, 529.24. found 529.2.(8-6)4-{6-[(2-mercaptomethyl-hexanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₅N₃O₃S, 482.24. found 482.2.(8-7)4-{6-[((R)-2-mercaptopentanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₅H₃₁N₃O₃S, 454.21. found 454.2.(8-8)4-{6-[((S)-2-mercaptopentanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₅H₃₁N₃O₃S, 454.21. found 454.2.(8-9)4-{6-[((S)-2-mercaptomethyl-3-methyl-butyrylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₃N₃O₃S, 468.22. found 468.2.(8-10)2-bromo-4-{6-[(3-cyclohexyl-2-mercaptomethyl-propionylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₈BrN₃O₃S, 600.18. found 601.2.(8-11)2-bromo-4-{6-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₂BrN₃O₃S, 546.13. found 547.2.(8-12)2-bromo-4-{6-[((S)-2-mercapto-4,4-dimethylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₄BrN₃O₃S, 560.15. found 561.2.(8-13)2-bromo-4-{4-methyl-2-propyl-6-[(5,5,5-trifluoro-2-mercaptopentanoyl-amino)methyl]-benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₅H₂₇BrF₃N₃O₃S, 586.09. found 587.2.(8-14)2-bromo-4-{6-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₄BrN₃O₃S, 560.15. found 561.2.(8-15)2-bromo-4-{6-[((S)-2-mercaptomethyl-3-methyl-butyrylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₂BrN₃O₃S, 546.13. found 547.2.(8-16)2-bromo-4-{6-[((S)-2-mercaptopentanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₅H₃₀BrN₃O₃S, 532.12. found 533.2.(8-17)2-bromo-4-{6-[((S)-2-mercapto-3-phenylpropionylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₀BrN₃O₃S, 580.12. found 581.2.(8-18)2-bromo-4-{6-[(2-mercaptomethyl-3-phenylpropionylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₂BrN₃O₃S, 594.13. found 595.2.(8-19)2-bromo-4-{6-[(2-mercaptomethylhexanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₄BrN₃O₃S, 560.15. found 561.2.(8-20)2-bromo-4-{6-[(2-mercaptomethyl-5-methylhexanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₆BrN₃O₃S, 574.17. found 575.2.(8-21)2-bromo-4-{6-[((R)-2-mercapto-4-methylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₂BrN₃O₃S, 546.13. found 547.2.(8-22)2-bromo-4-{6-[((R)-2-mercapto-4,4-dimethylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₄BrN₃O₃S, 560.15. found 561.2.(8-23)2-bromo-4-{6-[((R)-2-mercaptopentanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₅H₃₀BrN₃O₃S, 532.12. found 533.2.(8-24)2-bromo-4-{6-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₄BrN₃O₃S, 560.15. found 561.2.(8-25)4-{6-[((S)-2-mercapto-4-methylpentanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₃N₃O₃S, 468.22. found 468.2.(8-26)4-{6-[((5)-2-mercapto-4,4-dimethylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₅N₃O₃S, 482.24. found 482.2.(8-27)4-{4-methyl-2-propyl-6-[(5,5,5-trifluoro-2-mercaptopentanoylamino)methyl]-benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₅H₂₈F₃N₃O₃S, 508.18. found 508.2.(8-28)4-{4-methyl-2-propyl-6-[(6,6,6-trifluoro-2-mercaptohexanoylamino)methyl]-benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₀F₃N₃O₃S, 522.20. found 522.2.(8-29)4-{6-[((R)-2-mercapto-4-methylpentanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₃N₃O₃S, 468.22. found 468.2.(8-30)4-{6-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₅N₃O₃S, 482.24. found 482.2.(8-31)4-{6-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₅N₃O₃S, 482.24. found 482.2.(8-32)4-{6-[((R)-2-mercapto-4,4-dimethylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₅N₃O₃S, 482.24. found 482.2.(8-33)2-bromo-4-{6-[(2-mercaptomethyl-4-methylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₄BrN₃O₃S, 560.15. found 561.2.(8-34)2-fluoro-4-{6-[((S)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₄FN₃O₃S, 500.23. found 500.2.(8-35)2-fluoro-4-{6-[((S)-2-mercapto-4,4-dimethylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₄FN₃O₃S, 500.23. found 500.2.(8-36)2-fluoro-4-{4-methyl-2-propyl-6-[(5,5,5-trifluoro-2-mercaptopentanoylamino)-methyl]benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₅H₂₇F₄N₃O₃S, 526.17. found 526.2.(8-37)2-fluoro-4-{4-methyl-2-propyl-6-[(6,6,6-trifluoro-2-mercaptohexanoylamino)-methyl]benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₂₉F₄N₃O₃S, 540.19. found 540.2.(8-38)2-fluoro-4-{6-[((S)-2-mercaptopentanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₅H₃₀FN₃O₃S, 472.20. found 472.2.(8-39)2-fluoro-4-{6-[(2-mercaptomethyl-hexanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₄FN₃O₃S, 500.23. found 500.2.(8-40)2-fluoro-4-{6-[(2-mercaptomethyl-5-methyl-hexanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₈H₃₆FN₃O₃S, 514.25. found 514.2.(8-41)2-fluoro-4-{6-[(2-mercaptomethyl-3-methylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₄FN₃O₃S, 500.23. found 500.2.(8-42)4-{6-[(3-cyclopentyl-2-mercaptomethyl-propionylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₆FN₃O₃S, 526.25. found 526.2.(8-43)4-{6-[(3-cyclohexyl-2-mercaptomethyl-propionylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}-2-fluorobenzoicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₈FN₃O₃S, 540.26. found 540.2.(8-44)2-fluoro-4-{6-[(2-mercaptomethyl-3-phenylpropionylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₂FN₃O₃S, 534.22. found 534.2.(8-45)2-fluoro-4-{6-[((S)-2-mercapto-3-phenylpropionylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₀FN₃O₃S, 520.20. found 520.2.(8-46)2-fluoro-4-{6-[((R)-2-mercaptomethyl-4-methylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₄FN₃O₃S, 500.23. found 500.2.(8-47)2-fluoro-4-{6-[((S)-2-mercaptomethyl-3-methyl-butyrylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₂FN₃O₃S, 486.22. found 486.2.(8-48)2-fluoro-4-{6-[((R)-2-mercaptopentanoylamino)methyl]-4-methyl-2-propyl-benzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₅H₃₀FN₃O₃S, 472.20. found 472.2.(8-49)2-fluoro-4-{6-[((R)-2-mercapto-4,4-dimethylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₇H₃₄FN₃O₃S, 500.23. found 500.2.(8-50)2-fluoro-4-{6-[((R)-2-mercapto-4-methylpentanoylamino)methyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₂FN₃O₃S, 486.22. found 486.2.

Example 9

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds9-1 to 9-6, having the following formula, were also prepared:

Ex. R¹ R⁵ R⁶ 9-1 —COOH —CH₂—C(O)N(OH)H benzyl 9-2 —COOH —CH₂—N(OH)C(O)Hbenzyl 9-3 —CCCH —CH₂—N(OH)C(O)CH₃ benzyl 9-4 —COOCH₃ —CH₂—N(OH)C(O)Hbenzyl 9-5 —COOH —CH₂SH —CH₂CH(CH₃)₂ 9-6 —COOH —CH₂SH benzyl(9-1)4-[6-((R)-1-benzyl-2-hydroxycarbamoylethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]benzoicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₂N₄O₅, 529.24; found 529.6.(9-2)4-{6-[(R)-1-benzyl-2-(formylhydroxyamino)ethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₃₀H₃₂N₄O₅, 529.24. found 529.5.(9-3)4-{6-[(R)-2-(acetylhydroxyamino)-1-benzylethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₄N₄O₅, 543.25. found 543.2.(9-4)4-{6-[(R)-1-benzyl-2-(formylhydroxyamino)ethylcarbamoyl]-4-methyl-2-propylbenzoimidazol-1-ylmethyl}benzoicacid methyl ester. MS m/z: [M+H⁺] calcd for C₃₁H₃₄N₄O₅, 543.25. found543.3.(9-5)4-[6-((R)-1-mercaptomethyl-3-methylbutylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]-benzoicacid. MS m/z: [M+H⁺] calcd for C₂₆H₃₃N₃O₃S, 468.22. found 468.2.(9-6)4-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]-benzoicacid. MS m/z: [M+H⁺] calcd for C₂₉H₃₁N₃O₃S, 502.21. found 502.4.

Preparation 11 Dimer of 7-Methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)amide

7-Methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid (10 g, 40 mmol)and HATU (19.2 g, 50.4 mmol) were dissolved in DMF (21.4 mL, 276.7mmol), and stirred for 5 minutes at room temperature.(R)-1-((R)-2-Amino-4-methylpentyldisulfanyl-methyl)-3-methylbutylamine•2-[HCl](7.7 g, 22.9 mmol) was added, followed by DIPEA (18.0 mL, 103 mmol). Themixture was stirred at room temperature overnight. EtOAc (200 mL) wasadded and the mixture was washed with a saturated sodium bicarbonatesolution (100 mL) and saturated aqueous NaCl (2×100 mL). The organiclayer was dried over MgSO₄, filtered, and evacuated to dryness. Thereaction mixture was concentrated and the resulting crude solid waspurified by silica gel chromatography.

Preparation 12 4′-Bromomethylbiphenyl-2-sulfonic Acid1-dimethylaminometh-(E)-ylideneamide

2-Bromo-N—[1-dimethylaminometh-(E)-ylidene]benzenesulfonamide

1,1-Dimethoxy-N,N-dimethylmethanamine (14.6 mL, 104 mmol) was added to2-bromobenzene-1-sulfonamide (20.4 g, 86.4 mmol) in DMF (56 mL, 720mmol). The mixture was stirred at room temperature for about 90 minutes.A solution of sodium hydrogen sulfate (1.7 g, 14 mmol) in water (170 mL,9400 mmol) was cooled to 0° C. and then added to the mixture. Theprecipitate was filtered, washed with water, and dried to yield2-bromo-N-[1-dimethylaminometh-(E)-ylidene]benzenesulfonamide as a whitesolid (24.3 g).

4′-Methybiphenyl-2-sulfonic acid 1-dimethylaminometh-(E)-ylideneamide

2-Bromo-N-[1-dimethylaminometh-(E)-ylidene]benzenesulfonamide (5.36 g,18.4 mmol), 4-methylphenylboronic acid (5.0 g, 36.8 mmol), potassiumcarbonate (5.1 g, 36.8 mmol), water (19.7 mL, 1090 mmol), EtOH (49.2 mL,842 mmol) and toluene (98.3 mL, 923 mmol) were combined and the mixturewas stirred under nitrogen. Tetrakis(triphenylphosphine)palladium(0)(1.4 g, 1.2 mmol) was then added. The mixture was heated at 60° C. forabout 2 hours, then heated at 70° C. for 30 minutes. The mixture wasthen cooled to room temperature and water (100 mL) and EtOAc (100 mL)were added. The mixture was washed with saturated aqueous NaCl,extracted with EtOAc, dried over MgSO₄, filtered through Celite® andconcentrated to yield the crude product as a red solid (8.6 g). Thesolid material was triturated with 1:1 EtOAc:hexanes, filtered, andrinsed with hexanes to yield the crude product as a reddish-brown solid(6.2 g). The solid material was again triturated with EtOAc, filtered,and rinsed with EtOAc to yield 4′-methybiphenyl-2-sulfonic acid1-dimethylaminometh-(E)-ylideneamide as a light brown solid (4.6 g;96.2% purity).

Title Compound

4′-Methylbiphenyl-2-sulfonic acid 1-dimethylaminometh-(E)-ylideneamide(7.8 g, 26 mmol) was combined with NBS (4.6 g, 25.8 mmol), benzoylperoxide (31 mg, 130 μmol) and chlorobenzene (100 mL, 990 mmol). Themixture was heated at 95° C. The reaction was monitored until completion(about 2.5 hours). The mixture was then cooled to room temperature andwater was added. The mixture was extracted with DCM, washed with asaturated bicarbonate solution and saturated aqueous NaCl, extractedagain with DCM, dried over MgSO₄, filtered, and concentrated. The crudematerial (9.8 g) was combined with a second lot of crude material (1.7g) and taken up in DCM (40 mL). EtOAc (120 mL) was added. A few seedcrystals from a third lot of material were added and the mixture wasstored at −20° C. A precipitate formed, was filtered and rinsed withEtOAc. HPLC analysis of the resulting product, an off-white solid (8.7g) showed 17% starting material, 74% title compound, 7% dibromide.

Example 103-(2′-Acetylsulfamoylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)amide

Dimer of3-(2′-{([1-dimethylamino-meth-(E)-ylidene]-sulfamoyl}biphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)amide (10a): The7-methyl-2-propyl-3H-benzoimidazole-5-carboxylic acid((R)-1-mercaptomethyl-3-methylbutyl)amide dimer (2.5 g, 3.7 mmol) wasdissolved in DMF (50.0 mL, 646 mmol). The mixture was cooled to 0° C.,and sodium hydride (356 mg, 8.89 mmol) was added in portions.4′-Bromomethylbiphenyl-2-sulfonic acid1-dimethylaminometh-(E)-ylideneamide (4.0 g, 7.8 mmol) was added and themixture was stirred at 0° C. for 10 minutes, then warmed to roomtemperature. Water was added upon completion of the reaction (about 40minutes). The material was extracted 3× with DCM, washed with saturatedaqueous NaCl, dried over MgSO₄, filtered, and concentrated to yield 6.1g of crude intermediate 10a.

Dimer of7-methyl-2-propyl-3-(2′-sulfamoylbiphenyl-4-ylmethyl)-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)amide (10b): Intermediate 10awas taken up in EtOH (110 mL, 1800 mmol). Concentrated HCl (55.0 mL) wasadded and the mixture was heated at 70° C. for 4 hours, and at 75° C.for 30 minutes. The mixture was then cooled to room temperature. 6N NaOH(110 mL) was added to pH 13. Concentrated HCl (2 mL) was then added,maintaining the pH 13. The mixture was extracted with 3:1 CHCl₃:iPrOH(3×), washed with saturated aqueous NaCl, extracted again with 3:1CHCl₃:iPrOH, dried over MgSO₄, filtered, and concentrated to yield alight brown solid (4.8 g). The solid was taken up in EtOAc and a smallamount of MeOH, filtered and rinsed with EtOAc to yield a chunkyoff-white solid (1.8 g). The liquor and the solid were combined andtaken up in 3:1 CHCl₃:iPrOH and water. 1N HCl was added until pH ˜1.Saturated aqueous bicarbonate was added until pH ˜9. The product wasextracted with 3:1 CHCl₃:iPrOH (3×), washed with saturated aqueous NaCl,dried over MgSO₄, filtered, and concentrated to yield a yellow solid(4.3 g); this solid was taken up in EtOAc and a small amount of MeOH,filtered and rinsed with EtOAc to yield intermediate 10b as a powderyoff-white solid (1.4 g). The liquor was concentrated to yield a yellowsolid (2.6 g), which was purified by silica gel chromatography (120 g,0% to 10% to 40% MeOH in DCM) to yield a yellow solid (1.3 g); thissolid was taken up in EtOAc and a small amount of MeOH, filtered andrinsed with EtOAc to yield intermediate 10b as an off-white solid (0.5g).

Dimer of3-(2′-acetylsulfamoylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)amide (10c): Intermediate 10b(2 g, 1.7 mmol) was taken up in DCM (50.0 mL, 780 mmol) and THF (25.0mL, 308 mmol). DIPEA (1480 μL, 8.48 mmol) was added, followed by theaddition of 4-dimethylaminopyridine (518 mg, 4.2 mmol) and acetylchloride (724 μL, 10.2 mmol). The mixture was stirred at roomtemperature for 10 minutes. Additional DIPEA (592 μL, 2 eq) was added,followed by additional acetyl chloride (121 μL, 1 eq) and4-dimethylaminopyridine (52 mg, 0.25 eq). Water (50 mL) was added after10 minutes. The mixture was extracted with DCM (2×), washed withsaturated aqueous NaCl, dried over MgSO₄, filtered, and concentrated toyield crude intermediate 10c (3.0 g).

Intermediate 10c (3.0 g) was dissolved in THF (80 mL), andtris(2-carboxyethyl)phosphine hydrochloride (1460 mg, 5.1 mmol) in water(40 mL) was added. The mixture was stirred under nitrogen for 40minutes. The mixture was extracted with DCM (3×), washed with saturatedaqueous NaCl, dried over MgSO₄, filtered, concentrated, and purified bypreparative HPLC to yield the title compound as a white solid (1.3 g;99.6% purity). MS m/z: [M+H⁺] calcd for C₃₃H₄₀N₄O₄S₂, 621.25. found621.6.

Example 11

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds11-1 to 11-16, having the following formula, were also prepared:

Ex. R¹ R⁵ R⁶ 11-1 —SO₂NHC(O)-phenyl —CH₂SH benzyl 11-2 —SO₂NHC(O)CH₃—CH₂SH benzyl 11-3 —SO₂NHC(O)NHCH₂CH₃ —CH₂SH benzyl 11-4—SO₂NHC(O)(CH₂)₂CH₃ —CH₂SH benzyl 11-5 —SO₂NHC(O)CH₂OH —CH₂SH benzyl11-6 —SO₂NHC(O)CH₃ —CH₂N(OH)—CHO benzyl 11-7 —SO₂NHC(O)CH₂OH —CH₂SH—CH₂CH(CH₃)₂ 11-8 —SO₂NHC(O)CH(CH₃)(OH) —CH₂SH —CH₂CH(CH₃)₂ 11-9—SO₂NHC(O)C(CH₃)₂(OH) —CH₂SH —CH₂CH(CH₃)₂ 11-10 —SO₂NHC(O)CH₂OCH₃ —CH₂SH—CH₂CH(CH₃)₂ 11-11 —SO₂NHC(O)CH₂O(CH₂)₂OCH₃ —CH₂SH —CH₂CH(CH₃)₂ 11-12—SO₂NHC(O)CH₂N(CH₃)₂ —CH₂SH —CH₂CH(CH₃)₂ 11-13 —SO₂NHC(O)CH₂NH₂ —CH₂SH—CH₂CH(CH₃)₂ 11-14 —SO₂NHC(O)CH(CH₃)(NH₂) —CH₂SH —CH₂CH(CH₃)₂ 11-15—SO₂NHC(O)CH₂-morpholin-4-yl —CH₂SH —CH₂CH(CH₃)₂ 11-16—SO₂NHC(O)CH₂-4-acetyl- —CH₂SH —CH₂CH(CH₃)₂ piperazin-1-yl(11-1)3-(2′-benzoylsulfamoylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-benzyl-2-mercaptoethyl)amide. MS m/z: [M+H⁺] calcd forC₄H₄₀N₄O₄S₂, 717.25. found 717.5.(11-2)3-(2′-acetylsulfamoylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-benzyl-2-mercaptoethyl)amide. MS m/z: [M+H⁺] calcd forC₃₆H₃₈N₄O₄S₂, 655.23. found 655.6.(11-3) MS m/z: [M+H⁺] calcd for C₃₇H₄₁N₅O₄S₂, 684.26. found 684.6.(11-4)3-(2′-butyrylsulfamoylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-benzyl-2-mercapto-ethyl)amide. MS m/z: [M+H⁺] calcd forC₃₈H₄₂N₄O₄S₂, 683.27. found 683.6.(11-5)3-[2′-(2-hydroxyacetylsulfamoyl)-biphenyl-4-ylmethyl]-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-benzyl-2-mercapto-ethyl)amide. MS m/z: [M+H⁺] calcd forC₃₆H₃₈N₄O₅S₂, 671.23. found 671.6.(11-6)3-(2′-acetylsulfamoylbiphenyl-4-ylmethyl)-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid [(R)-1-benzyl-2-(formylhydroxyamino)ethyl]amide. MS m/z: [M+H⁺]calcd for C₃₇H₃₉N₅O₆S, 682.26. found 682.6.(11-7)3-[2′-(2-hydroxyacetylsulfamoyl)-biphenyl-4-ylmethyl]-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)amide. MS m/z: [M+H⁺] calcd forC₃₃H₄₀N₄O₅S₂, 637.24. found 637.4.(11-8)3-[2′-((S)-2-hydroxypropionylsulfamoyl)-biphenyl-4-ylmethyl]-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)amide. MS m/z: [M+H⁺] calcd forC₃₄H₄₂N₄O₅S₂, 651.26. found 651.2.(11-9)3-[2′-(2-hydroxy-2-methylpropionylsulfamoyl)-biphenyl-4-ylmethyl]-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)-amide. MS m/z: [M+H⁺] calcdfor C₃₅H₄₄N₄O₅S₂, 665.28. found 665.2.(11-10)3-[2′-(2-methoxyacetylsulfamoyl)biphenyl-4-ylmethyl]-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)amide. MS m/z: [M+H⁺] calcd forC₃₄H₄₂N₄O₅S₂, 651.26. found 651.4.(11-11)3-{2′-[2-(2-methoxyethoxy-acetylsulfamoyl]-biphenyl-4-ylmethyl}-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)-amide. MS m/z: [M+H⁺] calcdfor C₃₆H₄₆N₄O₆S₂, 695.29. found 695.6.(11-12)3-[2′-(2-dimethylaminoacetylsulfamoyl)-biphenyl-4-ylmethyl]-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)-amide. MS m/z: [M+H⁺] calcdfor C₃₅H₄₅N₅O₄S₂, 664.29. found 664.4.(11-13)3-[2′-(2-aminoacetylsulfamoyl)-biphenyl-4-ylmethyl]-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)-amide. MS m/z: [M+H⁺] calcdfor C₃₃H₄₁N₅O₄S₂, 636.26. found 636.2.(11-14)3-[2′-((S)-2-aminopropionylsulfamoyl)-biphenyl-4-ylmethyl]-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)-amide. MS m/z: [M+H⁺] calcdfor C₃₄H₄₃N₅O₄S₂, 650.28. found 650.6.(11-15)7-methyl-3-[2′-(2-morpholin-4-yl-acetylsulfamoyl)-biphenyl-4-ylmethyl]-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)-amide. MS m/z: [M+H⁺] calcdfor C₃₇H₄₇N₅O₅S₂, 706.30. found 706.8.(11-16)3-{2′-[2-(4-acetylpiperazin-1-yl)-acetylsulfamoyl]-biphenyl-4-ylmethyl}-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methyl-butyl)-amide. MS m/z: [M+H⁺] calcdfor C₃₉H₅₀N₆O₅S₂, 747.33. found 747.6.

Example 12

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds12-1 to 12-17, having the following formula, were also prepared:

Ex. R¹ R² R³ R⁵ R⁶ 12-1 —COOH absent —(CH₂)₂CH₃ —CH₂SH benzyl 12-2 —COOHabsent —(CH₂)₂CH₃ —CH₂SH —CH₂CH(CH₃)₂ 12-3 —COOH absent —OCH₂CH₃ —CH₂SHbenzyl 12-4 —COOH Cl —(CH₂)₂CH₃ —CH₂SH benzyl 12-5 —COOH Cl —(CH₂)₂CH₃—CH₂SH —CH₂CH(CH₃)₂ 12-6 —COOH —CF₃ —(CH₂)₂CH₃ —CH₂SH benzyl 12-7tetrazol-5-yl —CF₃ —(CH₂)₂CH₃ —CH₂SH benzyl 12-8 tetrazol-5-yl —CF₃—(CH₂)₂CH₃ —CH₂SH —CH₂CH(CH₃)₂ 12-9 tetrazol-5-yl —CF₃ —(CH₂)₂CH₃—CH₂—N(OH)CHO benzyl 12-10 tetrazol-5-yl Cl —(CH₂)₂CH₃ —CH₂SH benzyl12-11 tetrazol-5-yl Cl —(CH₂)₂CH₃ —CH₂SH —CH₂CH(CH₃)₂ 12-12tetrazol-5-yl Cl —(CH₂)₂CH₃ —CH₂—N(OH)CHO benzyl 12-13 tetrazol-5-yl Cl—(CH₂)₂CH₃ —CH₂—N(OH)CHO —CH₂CH(CH₃)₂ 12-14 —COOH —CH₂F —(CH₂)₂CH₃—CH₂SH benzyl 12-15 —COOH —CH₂F —(CH₂)₂CH₃ —CH₂SH —CH₂CH(CH₃)₂ 12-16—COOH —CH₂OH —(CH₂)₂CH₃ —CH₂SH benzyl 12-17 —COOH —CH₂OH —(CH₂)₂CH₃—CH₂SH —CH₂CH(CH₃)₂(12-1)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₄H₃₃N₃O₃S, 564.22; found 564.6.(12-2)4′-[6-((R)-1-mercaptomethyl-3-methyl-butylcarbamoyl)-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₅N₃O₃S, 530.24. found 530.6.(12-3)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-2-ethoxybenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₃H₃₁N₃O₄S, 566.20; found 566.5.(12-4)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-chloro-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₄H₃₂ClN₃O₃S, 598.19. found 598.6.(12-5)4′-[4-chloro-6-((R)-1-mercaptomethyl-3-methylbutylcarbamoyl)-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₄ClN₃O₃S, 564.20. found 564.2.(12-6)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-2-propyl-4-trifluoromethyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₂F₃N₃O₃S, 632.21. found 632.4.(12-7)2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-7-trifluoromethyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-benzyl-2-mercaptoethyl)amide. MS m/z: [M+H⁺] calcd forC₃₅H₃₂F₃N₇OS, 656.23. found 656.6.(12-8)2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-7-trifluoromethyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)amide. MS m/z: [M+H⁺] calcd forC₃₂H₃₄F₃N₇OS, 622.25. found 622.6.(12-9)2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-7-trifluoromethyl-3H-benzoimidazole-5-carboxylicacid [(R)-1-benzyl-2-(formylhydroxyamino)ethyl]amide. MS m/z: [M+H⁺]calcd for C₃₆H₃₃F₃N₈O₃, 683.26. found 683.6.(12-10)7-chloro-2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazole-5-carboxylicacid ((R)-1-benzyl-2-mercaptoethyl)amide. MS m/z: [M+H⁺] calcd forC₃₄H₃₂ClN₇OS, 622.21. found 622.5.(12-11)7-chloro-2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)amide. MS m/z: [M+H⁺] calcd forC₃₁H₃₄ClN₇OS, 588.22. found 588.6.(12-12)7-chloro-2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazole-5-carboxylicacid [(R)-1-benzyl-2-(formylhydroxyamino)ethyl]amide. MS m/z: [M+H⁺]calcd for C₃₅H₃₃ClN₈O₃, 649.24. found 649.8.(12-13)7-chloro-2-propyl-3-[2′-(1H-tetrazol-5-yl)-biphenyl-4-ylmethyl]-3H-benzoimidazole-5-carboxylicacid {(R)-1-[(formylhydroxyamino)methyl]-3-methylbutyl}amide. MS m/z:[M+H⁺] calcd for C₃₂H₃₅ClN₈O₃, 615.25. found 615.4.(12-14)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-fluoromethyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₄FN₃O₃S, 596.23. found 596.6.(12-15)4′-[4-fluoromethyl-6-((R)-1-mercaptomethyl-3-methyl-butylcarbamoyl)-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₆FN₃O₃S, 562.25. found 562.4.(12-16)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-hydroxymethyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₅N₃O₄S, 594.24. found 594.4.(12-17)4′-[4-hydroxymethyl-6-((R)-1-mercaptomethyl-3-methylbutylcarbamoyl)-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₇N₃O₄S, 560.25. found 560.4.

Example 13

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds13-1 to 13-8, having the following formula, were also prepared:

Ex. R R⁶ 13-1 2′-Cl benzyl 13-2 2′-F benzyl 13-3 3′-Cl benzyl 13-4 3′-Fbenzyl 13-5 2′-F —CH₂CH(CH₃)₂ 13-6 2′-Cl —CH₂CH(CH₃)₂ 13-7 3′-Cl—CH₂CH(CH₃)₂ 13-8 3′-F —CH₂CH(CH₃)₂(13-1)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]-2′-chlorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₄ClN₃O₃S, 612.20. found 612.2.(13-2)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]-2′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₄FN₃O₃S, 596.23. found 596.2.(13-3)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]-3′-chlorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₄ClN₃O₃S, 612.20. found 612.2.(13-4)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]-3′-fluorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₄FN₃O₃S, 596.23. found 596.2.(13-5)2′-fluoro-4′-[6-((R)-1-mercaptomethyl-3-methylbutylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₆FN₃O₃S, 562.25. found 562.2.(13-6)2′-chloro-4′-[6-((R)-1-mercaptomethyl-3-methylbutylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₆ClN₃O₃S, 578.22. found 578.2.(13-7)3′-chloro-4′-[6-((R)-1-mercaptomethyl-3-methylbutylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₆ClN₃O₃S, 578.22. found 578.2.(13-8)3′-fluoro-4′-[6-((R)-1-mercaptomethyl-3-methylbutylcarbamoyl)-4-methyl-2-propylbenzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₆FN₃O₃S, 562.25. found 562.2.

Example 14

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds14-1 to 14-7, having the following formula, were also prepared:

Ex. R R⁶ 14-1 3-Cl benzyl 14-2 4-Cl benzyl 14-3 5-Cl benzyl 14-4 6-Clbenzyl 14-5 3-Cl —CH₂CH(CH₃)₂ 14-6 4-Cl —CH₂CH(CH₃)₂ 14-7 5-Cl—CH₂CH(CH₃)₂(14-1)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]-3-chlorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₄ClN₃O₃S; 612.20 found 612.2.(14-2)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]-4-chlorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₄ClN₃O₃S, 612.20. found 612.2.(14-3)4′-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]-5-chlorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₄ClN₃O₃S, 612.20. found 612.2.(14-4)4′-[6-((R)-1-benzyl-2-mercapt-ethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]-6-chlorobiphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₅H₃₄ClN₃O₃S, 612.20. found 612.2.(14-5)3-chloro-4′-[6-((R)-1-mercaptomethyl-3-methylbutylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]-biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₆ClN₃O₃S, 578.22. found 578.2.(14-6)4-chloro-4′-[6-((R)-1-mercaptomethyl-3-methylbutylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₆ClN₃O₃S, 578.22. found 578.2.(14-7)5-chloro-4′-[6-((R)-1-mercaptomethyl-3-methylbutylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]biphenyl-2-carboxylicacid. MS m/z: [M+H⁺] calcd for C₃₂H₃₆ClN₃O₃S, 578.22. found 578.2.

Example 15

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds15-1 to 15-4, having the following formula, were also prepared:

Ex. R¹ R⁶ 15-1 —COOH benzyl 15-2 —COOH —CH₂CH(CH₃)₂ 15-3 —SO₂NHC(O)CH₃benzyl 15-4 —SO₂NHC(O)CH₃ —CH₂CH(CH₃)₂(15-1)2-{5-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]-pyridin-2-yl}benzoicacid. MS m/z: [M+H⁺] calcd for C₃₄H₃₄N₄O₃S, 579.24. found 579.5.(15-2)2-{5-[6-((R)-1-mercaptomethyl-3-methylbutylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]-pyridin-2-yl}benzoicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₆N₄O₃S, 545.25. found 545.5.(15-3)3-[6-(2-acetylsulfamoylphenyl)-pyridin-3-ylmethyl]-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-benzyl-2-mercaptoethyl)amide. MS m/z: [M+H⁺] calcd forC₃₅H₃₇N₅O₄S₂, 656.23. found 656.4.(15-4)3-[6-(2-acetylsulfamoylphenyl)-pyridin-3-ylmethyl]-7-methyl-2-propyl-3H-benzoimidazole-5-carboxylicacid ((R)-1-mercaptomethyl-3-methylbutyl)amide. MS m/z: [M+H⁺] calcd forC₃₂H₃₉N₅O₄S₂, 622.24. found 622.5.

Example 16

Following the procedures described in the examples above, andsubstituting the appropriate starting materials and reagents, compounds16-1 to 16-2, having the following formula, were also prepared:

Ex. R⁶ 16-1 —CH₂CH(CH₃)₂ 16-2 benzyl(16-1)2-{6-[6-((R)-1-mercaptomethyl-3-methylbutylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]-pyridin-3-yl}benzoicacid. MS m/z: [M+H⁺] calcd for C₃₁H₃₆N₄O₃S, 545.25. found 545.6.(16-2)2-{6-[6-((R)-1-benzyl-2-mercaptoethylcarbamoyl)-4-methyl-2-propyl-benzoimidazol-1-ylmethyl]-pyridin-3-yl}benzoicacid. MS m/z: [M+H⁺] calcd for C₃₄H₃₄N₄O₃S, 579.24. found 579.4.

Assay 1 AT₁ and AT₂ Radioligand Binding Assays

These in vitro assays were used to assess the ability of test compoundsto bind to the AT₁ and the AT₂ receptors.

Membrane Preparation From Cells Expressing Human AT₁ or AT₂ Receptors

Chinese hamster ovary (CHO-K¹) derived cell lines stably expressing thecloned human AT₁ or AT₂ receptors, respectively, were grown in HAM's-F12medium supplemented with 10% fetal bovine serum, 10 μg/mlpenicillin/streptomycin, and 500 μg/ml geneticin in a 5% CO₂ humidifiedincubator at 37° C. AT₂ receptor expressing cells were grown in theadditional presence of 100 nM PD123,319 (AT₂ antagonist). When culturesreached 80-95% confluence, the cells were washed thoroughly in PBS andlifted with 5 mM EDTA. Cells were pelleted by centrifugation and snapfrozen in MeOH-dry ice and stored at −80° C. until further use.

For membrane preparation, cell pellets were resuspended in lysis buffer(25 mM Tris/HCl pH 7.5 at 4° C., 1 mM EDTA, and one tablet of CompleteProtease Inhibitor Cocktail Tablets with 2 mM EDTA per 50 mL buffer(Roche cat.#1697498, Roche Molecular Biochemicals, Indianapolis, Ind.))and homogenized using a tight-fitting Dounce glass homogenizer (10strokes) on ice. The homogenate was centrifuged at 1000×g, thesupernatant was collected and centrifuged at 20,000×g. The final pelletwas resuspended in membrane buffer (75 mM Tris/HCl pH 7.5, 12.5 mMMgCl₂, 0.3 mM EDTA, 1 mM EGTA, 250 mM sucrose at 4° C.) and homogenizedby extrusion through a 20G gauge needle. Protein concentration of themembrane suspension was determined by the method described in Bradford(1976) Anal Biochem. 72:248-54. Membranes were snap frozen in MeOH-dryice and stored at −80° C. until further use.

Ligand Binding Assay to Determine Compound Affinities for the Human AT₁and AT₂ Angiotensin Receptors

Binding assays were performed in 96-well Acrowell filter plates (PallInc., cat.#5020) in a total assay volume of 100 μL with 0.2 μg membraneprotein for membranes containing the human AT₁ receptor, or 2 μgmembrane protein for membranes containing the human AT₂ receptor inassay buffer (50 mM Tris/HCl pH 7.5 at 20° C., 5 mM MgCl₂, 25 μM EDTA,0.025% BSA). Saturation binding studies for determination of K_(d)values of the ligand were done using N-terminally Europium-labeledangiotensin-II ([Eu]AngII,H-(Eu-N¹)-Ahx-Asp-Arg-Val-Tyr-Ile-His-Pro-Phe-OH; PerkinElmer, Boston,Mass.) at 8 different concentrations ranging from 0.1 nM to 30 nM.Displacement assays for determination of pK; values of test compoundswere done with [Eu]AngII at 2 nM and 11 different concentrations of drugranging from 1 μM to 10 μM. Drugs were dissolved to a concentration of 1mM in DMSO and from there serially diluted into assay buffer.Non-specific binding was determined in the presence of 10 μM unlabeledangiotensin-II. Assays were incubated for 120 minutes in the dark, atroom temperature or 37° C., and binding reactions were terminated byrapid filtration through the Acrowell filter plates followed by threewashes with 200 μL ice cold wash buffer (50 mM Tris/HCl pH 7.5 at 4° C.,5 mM MgCl₂) using a Waters filtration manifold. Plates were tapped dryand incubated with 50 μl DELFIA Enhancement Solution (PerkinElmercat.#4001-0010) at room temperature for 5 minutes on a shaker.Filter-bound [Eu]AngII was quantitated immediately on a Fusion platereader (PerkinElmer) using Time Resolved Fluorescence (TRF). Bindingdata were analyzed by nonlinear regression analysis with the GraphPadPrism Software package (GraphPad Software, Inc., San Diego, Calif.)using the 3-parameter model for one-site competition. The BOTTOM (curveminimum) was fixed to the value for nonspecific binding, as determinedin the presence of 10 μM angiotensin II. K_(i) values for drugs werecalculated from observed IC₅₀ values and the K_(d) value of [Eu]AngIIaccording to the Cheng-Prusoff equation described in Cheng et al. (1973)Biochem Pharmacol. 22(23):3099-108. Selectivities of test compounds forthe AT₁ receptor over the AT₂ receptor were calculated as the ratio ofAT₂K_(i)/AT₁K_(i). Binding affinities of test compounds were expressedas negative decadic logarithms of the K_(i) values (pK_(i)).

In this assay, a higher pK_(i) value indicates that the test compoundhas a higher binding affinity for the receptor tested. Exemplarycompounds of the invention that were tested in this assay, typicallywere found to have a pK_(i) at the AT₁ receptor greater than or equal toabout 5.0. For example, the compound of Example 1 was found to have apK_(i) value greater than about 7.0.

Assay 2 In Vitro Assays for the Quantitation of Inhibitor Potencies(IC₅₀) at Human and Rat NEP, and Human ACE

The inhibitory activities of compounds at human and rat NEP and humanACE were determined using in vitro assays as described below.

Extraction of NEP Activity from Rat Kidneys

Rat NEP was prepared from the kidneys of adult Sprague Dawley rats.Whole kidneys were washed in cold PBS and brought up in ice-cold lysisbuffer (1% Triton X-114, 150 mM NaCl, 50 mM Tris pH 7.5; Bordier (1981)J. Biol. Chem. 256:1604-1607) in a ratio of 5 mL of buffer for everygram of kidney. Samples were homogenized using a polytron hand heldtissue grinder on ice. Homogenates were centrifuged at 1000×g in aswinging bucket rotor for 5 minutes at 3° C. The pellet was resuspendedin 20 mL of ice cold lysis buffer and incubated on ice for 30 minutes.Samples (15-20 mL) were then layered onto 25 mL of ice-cold cushionbuffer (6% w/v sucrose, 50 mM pH 7.5 Tris, 150 mM NaCl, 0.06%, TritonX-114), heated to 37° C. for 3-5 minutes and centrifuged at 1000×g in aswinging bucket rotor at room temperature for 3 minutes. The two upperlayers were aspirated off, leaving a viscous oily precipitate containingthe enriched membrane fraction. Glycerol was added to a concentration of50% and samples were stored at −20° C. Protein concentrations werequantitated using a BCA detection system with BSA as a standard.

Enzyme Inhibition Assays

Recombinant human NEP and recombinant human ACE were obtainedcommercially (R&D Systems, Minneapolis, Minn., catalog numbers 1182-ZNand 929-ZN, respectively). The fluorogenic peptide substrate Mca-BK2(Mca-Arg-Pro-Pro-Gly-Phe-Ser-Ala-Phe-Lys(Dnp)-OH; Johnson et al. (2000)Anal. Biochem. 286: 112-118) was used for the human NEP and ACE assays,and Mca-RRL (Mca-DArg-Arg-Leu-(Dnp)-OH; Medeiros et al. (1997) Braz. J.Med. Biol. Res. 30:1157-1162) was used for the rat NEP assay (both fromAnaspec, San Jose, Calif.).

The assays were performed in 384-well white opaque plates at roomtemperature using the respective fluorogenic peptides at a concentrationof 10 μM in assay buffer (50 mM Tris/HCl at 25° C., 100 mM NaCl, 0.01%Tween-20, 1 μM Zn, 0.025% BSA). Human NEP and human ACE were used atconcentrations that resulted in quantitative proteolysis of 5 μM ofMca-BK2 within 20 minutes at room temperature. The rat NEP enzymepreparation was used at a concentration that yielded quantitativeproteolysis of 3 μM of Mca-RRL within 20 minutes at room temperature.

Assays were started by adding 25 μL of enzyme to 12.5 μL of testcompound at 12 concentrations (10 μM to 20 pM). Inhibitors were allowedto equilibrate with the enzyme for 10 minutes before 12.5 μL of thefluorogenic substrates were added to initiate the reaction. Reactionswere terminated by the addition of 10 μL of 3.6% glacial acetic acidafter 20 minutes of incubation. Plates were read on a fluorometer withexcitation and emission wavelengths set to 320 nm and 405 nm,respectively.

Raw data (relative fluorescence units) were normalized to % activityfrom the average high readings (no inhibition, 100% enzyme activity) andaverage low readings (full inhibition, highest inhibitor concentration,0% enzyme activity) using three standard NEP and ACE inhibitors,respectively. Nonlinear regression of the normalized data was performedusing a one site competition model (GraphPad Software, Inc., San Diego,Calif.). Data were reported as pIC₅₀ values.

Exemplary compounds of the invention that were tested in this assay,typically were found to have a pIC₅₀ for the NEP enzyme greater than orequal to about 5.0, for example, the compound of Example 1 has a pIC₅₀value greater than or equal to about 7.0.

Assay 3 Pharmacodynamic (PD) Assay for ACE, AT₁, and NEP Activity inAnesthetized Rats

Male, Sprague Dawley, normotensive rats are anesthetized with 120 mg/kg(i.p.) of inactin. Once anesthetized, the jugular vein, carotid artery(PE 50 tubing) and bladder (URI-1 urinary silicone catheter) arecannulated and a tracheotomy is performed (Teflon Needle, size 14 gauge)to faciliate spontaneous respiration. The animals are then allowed a 60minute stablization period and kept continuously infused with 5 mL/kg/hof saline (0.9%) throughout, to keep them hydrated and ensure urineproduction. Body temperature is maintained throughout the experiment byuse of a heating pad. At the end of the 60 minute stabilization period,the animals are dosed intravenously (i.v.) with two doses of angiotensin(AngI, 1.0 μg/kg, for ACE inhibitor activity; AngII, 0.1 μg/kg, for AT₁receptor antagonist activity) at 15 minutes apart. At 15 minutespost-second dose of angiotensin (AngI or AnglI), the animals are treatedwith vehicle or test compound. Five minutes later, the animals areadditionally treated with a bolus i.v. injection of atrial natriureticpeptide (ANP; 30 μg/kg). Urine collection (into pre-weighted eppendorftubes) is started immediately after the ANP treatment and continued for60 minutes. At 30 and 60 minutes into urine collection, the animals arere-challenged with angiotensin (AngI or AngII). Blood pressuremeasurements are done using the Notocord system (Kalamazoo, Mich.).Urine samples are frozen at −20° C. until used for the cGMP assay. UrinecGMP concentrations are determined by Enzyme Immuno Assay using acommercial kit (Assay Designs, Ann Arbor, Mich., Cat. No. 901-013).Urine volume is determined gravimetrically. Urinary cGMP output iscalculated as the product of urine output and urine cGMP concentration.ACE inhibition or AT₁ antagonism is assessed by quantifying the %inhibition of pressor response to AngI or AngII, respectively. NEPinhibition is assessed by quantifying the potentiation of ANP-inducedelevation in urinary cGMP output.

ASSAY 4 In Vivo Evaluation of Antihypertensive Effects in the ConsciousSHR Model of Hypertension

Spontaneously hypertensive rats (14-20 weeks of age) are allowed aminimum of 48 hours acclimation upon arrival at the testing site. Sevendays prior to testing, the animals are either placed on a restrictedlow-salt diet with food containing 0.1% of sodium for sodium depletedSHRs (SD-SHR) or are placed on a normal diet for sodium repleted SHRs(SR—SHR). Two days prior to testing, the animals are surgicallyimplemented with catheters into a carotid artery and the jugular vein(PE50 polyethylene tubing) connected via a PE10 polyethylene tubing to aselected silicone tubing (size 0.020 ID×0.037 OD×0.008 wall) for bloodpressure measurement and test compound delivery, respectively. Theanimals are allowed to recover with appropriate post operative care.

On the day of the experiment, the animals are placed in their cages andthe catheters are connected via a swivel to a calibrated pressuretransducer. After 1 hour of acclimation, a baseline measurement is takenover a period of at least 5 minutes. The animals are then dosed i.v.with vehicle or test compound in ascending cumulative doses every 60minutes followed by a 0.3 mL saline to clear the catheter after eachdose. Data is recorded continuously for the duration of the study usingNotocord software (Kalamazoo, Mich.) and stored as electronic digitalsignals. In some studies, the effects of a single i.v. or oral (gavage)dose are monitored for at least 6 hours after dosing. Parametersmeasured are blood pressure (systolic, diastolic and mean arterialpressure) and heart rate.

ASSAY 5 In Vivo Evaluation of Antihypertensive Effects in the ConsciousDOCA-Salt Rat Model of Hypertension

CD rats (male, adult, 200-300 grams, Charles River Laboratory, USA) areallowed a minimum of 48 hours acclimation upon arrival at the testingsite before they are placed on a high salt diet.

One week after the start of the high salt diet, a DOCA-salt pellet (100mg, 21 days release time, Innovative Research of America, Sarasota,Fla.) is implanted subcutaneously and unilateral nephrectomy isperformed. On 16 or 17 days post DOCA-salt pellet implantation, animalsare implanted surgically with catheters into a carotid artery and thejugular vein with a PE50 polyethylene tubing, which in turn wasconnected via a PE10 polyethylene tubing to a selected silicone tubing(size 0.020 ID×0.037 OD×0.008 wall) for blood pressure measurement andtest compound delivery, respectively. The animals are allowed to recoverwith appropriate post operative care.

On the day of the experiment, each animal is kept in its cage andconnected via a swivel to a calibrated pressure transducer. After 1 hourof acclimation, a baseline measurement is taken over a period of atleast five minutes. The animals are then dosed i.v. with a vehicle ortest compound in escalating cumulative doses every 60 minutes followedby 0.3 mL of saline to flush the catheter after each dose. In somestudies, the effects of a single intravenous or oral (gavage) dose istested and monitored for at least 6 hours after dosing. Data is recordedcontinuously for the duration of the study using Notocord software(Kalamazoo, Mich.) and stored as electronic digital signals. Parametersmeasured are blood pressure (systolic, diastolic and mean arterialpressure) and heart rate. For cumulative and single dosing, thepercentage change in mean arterial pressure (MAP, mm-Hg) or heart rate(HR, bpm) is determined as described for Assay 4.

While the present invention has been described with reference tospecific aspects or embodiments thereof, it will be understood by thoseof ordinary skilled in the art that various changes can be made orequivalents can be substituted without departing from the true spiritand scope of the invention. Additionally, to the extent permitted byapplicable patent statues and regulations, all publications, patents andpatent applications cited herein are hereby incorporated by reference intheir entirety to the same extent as if each document had beenindividually incorporated by reference herein.

What is claimed is:
 1. A compound of formula I:

wherein: r is 0, 1 or 2; Ar is:

R¹ is selected from —COOR^(1a), —NHSO₂R^(1b), —SO₂NHR^(1d), —SO₂OH,—C(O)NH—SO₂R^(1c), —P(O)(OH)₂, —CN, —OCH(R^(1e))—COOH, tetrazol-5-yl,

where R^(1a) is H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl,—C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl, —CH(C₁₋₄alkyl)OC(O)R^(1a),—C₀₋₆alkylenemorpholine,

R^(1aa) is —O—C₁₋₆alkyl, —O—C₃₋₇cycloalkyl, —NR^(1ab)R^(1ac), or—CH(NH₂)CH₂COOCH₃; R^(1ab) and R^(1ac) are independently selected fromH, —C₁₋₆alkyl, and benzyl, or are taken together as —(CH₂)₃₋₆—; R^(1b)is R^(1c) or —NHC(O)R^(1c); R^(1c) is —C₁₋₆alkyl,—C₀₋₆alkylene-O—R^(1ca), —C₁₋₅alkylene-NR^(1cb)R^(1cc),—C₀₋₄alkylenearyl or —C₀₋₄alkyleneheteroaryl; R^(1ca) is H, —C₁₋₆alkyl,or —C₁₋₆alkylene-O—C₁₋₆alkyl; R^(1cb) and R^(1cc) are independentlyselected from H and —C₁₋₆alkyl, or are taken together as—(CH₂)₂—O—(CH₂)₂— or —(CH₂)₂—N[C(O)CH₃]—(CH₂)₂—; R^(1d) is H, R^(1c),—C(O)R^(1c), or —C(O)NHR^(1c); R^(le) is —C₁₋₄alkyl or aryl; n is 0, 1,2 or 3; each R² is independently selected from halo, —NO₂, —C₁₋₆alkyl,—C₂₋₆alkenyl, —C₃₋₆cycloalkyl, —CN, —C(O)R^(2a), —C₀₋₅alkylene-OR^(2b),—C₀₋₅alkylene-NR^(2c)R^(2d), —C₀₋₃alkylenearyl, and—C₀₋₃alkyleneheteroaryl; where R^(2a) is H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl,—OR^(2b), or —NR^(2c)R^(2d); R^(2b) is H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl,or —C₀₋₁alkylenearyl; and R^(2c) and R^(2d) are independently selectedfrom H, —Cl₁₋₄alkyl, and —C₀₋₁alkylenearyl; R³ is selected from—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₃₋₁₀alkynyl, —C₀₋₃alkylene-C₃₋₇cycloalkyl,—C₂₋₃alkenylene-C₃₋₇cycloalkyl, —C₂₋₃alkynylene-C₃₋₇cycloalkyl,—C₀₋₅alkylene-NR^(3a)—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-S—C₁₋₅alkylene-R^(3b), and —C₀₋₃alkylenearyl; where R^(3a)is H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, or —C₀₋₃alkylenearyl; and R^(3b) isH, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, or aryl; Xis —C₁₋₁₂alkylene-, where at least one —CH₂— moiety in the alkylene isreplaced with a —NR^(4a)—C(O)— or —C(O)—NR^(4a)— moiety, where R^(4a) isH, —OH, or —C₁₋₄alkyl; R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), and —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d);where R^(5a) is H or —C(O)—R^(5aa); R^(5aa) is —C₁₋₆alkyl,—C₀₋₆alkylene-C₃₋₇cycloalkyl, -aminoC₄₋₇cycloalkyl, —C₀₋₆alkylenearyl,—C₀₋₆alkyleneheteroaryl, —C₀₋₆alkylenemorpholine,—C₀₋₆alkylenepiperazine-CH₃, —C₀₋₆alkylenepiperidine,—C₀₋₆alkylenepiperidine-CH₃, —CH[N(R^(5ab))₂]-aa where aa is an aminoacid side chain, —C₀₋₆alkylene-CH[N(R^(5ab))₂]—R^(5ac), -2-pyrrolidine,-2-tetrahydrofuran, —C₀₋₆alkylene-OR^(5ab), —O—C₀₋₆alkylenearyl,—C₁₋₂alkylene-OC(O)—C₁₋₆alkyl, —C₁₋₂alkylene-OC(O)—C₀₋₆alkylenearyl,—O—C₁₋₂alkylene-OC(O)O—C₁₋₆alkyl, —C₁₋₄alkylene-COOH, or -arylene-COOH;R^(5ab) is independently H or —C₁₋₆alkyl; R^(5ac) is H, —C₁₋₆alkyl,—CH₂—C₃₋₇cycloalkyl or —COOH; R^(5b) is H, —OH, —OC(O)R^(5ba), —CH₂COOH,—O-benzyl, -pyridyl, or —OC(S)NR^(5bb)R^(5bc); R^(5ba) is H, —C₁₋₆alkyl,aryl, —OCH₂-aryl, —CH₂O-aryl, or —NR^(5bb)R^(5bc); R^(5bb) and R^(5bc)are independently selected from H and —C₁₋₄alkyl; R^(5c) is H,—C₁₋₆alkyl, or —C(O)R^(5ca); R^(5ca) is —C₁₋₆alkyl, —C₃₋₇cycloalkyl,aryl, or heteroaryl; R^(5d) is H, —C₁₋₄alkyl, —C₀₋₃alkylenearyl,—NR^(5da)R^(5db), —CH₂SH, or —O—C₁₋₆alkyl; R^(5da) and R^(5db) areindependently selected from H and —C₁₋₄alkyl; R⁶ is selected from—C₁₋₆alkyl, —CH₂O(CH₂)₂OCH₃, —C₁₋₆alkylene-O—C₁₋₆alkyl,—C₀₋₃alkylenearyl, —C₀₋₃alkyleneheteroaryl, and—C₀₋₃alkylene-C₃₋₇cycloalkyl; and R⁷ is H or is taken together with R⁶to form —C₃₋₈cycloalkyl; wherein: each —CH₂— group in —(CH₂)_(r)— isoptionally substituted with 1 or 2 substituents independently selectedfrom —Cl₁₋₄alkyl and fluoro; each carbon atom in the alkylene moiety inX is optionally substituted with one or more R^(4b) groups and one —CH₂—moiety in X may be replaced with a group selected from—C₃₋₈cycloalkylene-, —CR^(4d)═CH—, and —CH═CR^(4d)—; where R^(4b) is—C₀₋₅alkylene-COOR^(4c), —C₁₋₆alkyl, —C₀₋₁alkylene-CONH₂,—C₁₋₂alkylene-OH, —C₀₋₃alkylene-C₃₋₇cycloalkyl, 1H-indol-3-yl, benzyl,or hydroxybenzyl; R^(4c) is H or —C₁₋₄alkyl; and R^(4d) is—CH₂-thiophene or phenyl; each alkyl and each aryl in R¹⁻³, R^(4a-4d),and R⁵⁻⁶ is optionally substituted with 1 to 7 fluoro atoms; Ar and eacharyl and heteroaryl in R¹⁻³ and R⁵⁻⁶ is optionally substituted with 1 to3 substituents independently selected from —OH, —C₁₋₆alkyl,—C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,—S—C₁₋₆alkyl, —S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, -phenyl, —NO₂, —NH₂,—NH—C₁₋₆alkyl and —N(C₁₋₆alkyl)₂, wherein each alkyl, alkenyl andalkynyl is optionally substituted with 1 to 5 fluoro atoms; andpharmaceutically acceptable salts thereof.
 2. The compound of claim 1,wherein r is
 1. 3. The compound of claim 1, wherein Ar is optionallysubstituted with one fluoro, chloro or bromo atom.
 4. The compound ofclaim 1, wherein R¹ is selected from —COOH, —NHSO₂R^(1b), —SO₂NHR^(1d),—SO₂OH, —C(O)NH—SO₂R^(1c), —P(O)(OH)₂, —CN, —O—CH(R^(1e))—COOH,tetrazol-5-yl,


5. The compound of claim 4, wherein R¹ is selected from —COOH,—SO₂NHR^(1d), and tetrazol-5-yl.
 6. The compound of claim 1, wherein R¹is —COOR^(1a) and R^(1a) is selected from —C₁₋₆alkyl, —C₁₋₃alkylenearyl,—C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl, —CH(C₁₋₄alkyl)OC(O)R^(1aa),—C₀₋₆alkylenemorpholine,


7. The compound of claim 1, wherein n is 0 or
 1. 8. The compound ofclaim 7, wherein n is 1 and R² is at the 4 position of thebenzoimidazole ring.
 9. The compound of claim 1, wherein R² is selectedfrom halo, —C₁₋₆alkyl, and —C₀₋₅alkylene-OR^(2b).
 10. The compound ofclaim 9, wherein R² is selected from chloro, —CH₃, —CH₂F, —CF₃, and—CH₂OH.
 11. The compound of claim 1, wherein R³ is selected from—C₁₋₁₀alkyl and —C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b), and R^(3b) is—C₁₋₆alkyl.
 12. The compound of claim 11, wherein R³ is —C₂₋₅alkyl. 13.The compound of claim 1, wherein X is —C₁₋₆alkylene- and one to four—CH₂— moieties are replaced with a —NR^(4a)—C(O)— or —C(O)—NR^(4a)—moiety.
 14. The compound of claim 13, wherein X is selected from—C(O)NH—, —NHC(O)—, and —CH₂—NHC(O)—.
 15. The compound of claim 1,wherein R^(5a) is H; R^(5b) is —OH; R^(5c) is H; and R^(5d) is H. 16.The compound of claim 1, wherein R^(5a) is —C(O)—R^(5aa); and R^(5b) isH, —OC(O)R^(5ba), —CH₂COOH, —O-benzyl, -pyridyl, or—OC(S)NR^(5bb)R^(5bc).
 17. The compound of claim 15, wherein R¹ isselected from —COOH, —NHSO₂R^(1b), —SO₂NHR^(1d), —SO₂OH,—C(O)NH—SO₂R^(1c), —P(O)(OH)₂, —CN, —O—CH(R^(1e))—COOH, tetrazol-5-yl,


18. The compound of claim 16, wherein R¹ is —COOR^(1a), and R^(1a) isselected from —C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₁₋₃alkyleneheteroaryl,—C₃₋₇cycloalkyl, —CH(C₁₋₄alkyl)-OC(O)R^(1aa), —C₀₋₆alkylenemorpholine,


19. The compound of claim 15, wherein R¹ is —COOR^(1a), and R^(1a) isselected from —C₁₋₆alkyl, —C₁₋₃alkylenearyl, —C₃alkyleneheteroaryl,—C₃₋₇cycloalkyl, —CH(C₁₋₄alkyl)-OC(O)R^(1aa), —C₀₋₆alkylenemorpholine,


20. The compound of claim 16, wherein R¹ is selected from —COOH,—NHSO₂R^(1b), —SO₂NHR^(1d), —SO₂OH, —C(O)NH—SO₂R^(1c), —P(O)(OH)₂, —CN,—O—CH(R^(1e))—COOH, tetrazol-5-yl,


21. The compound of claim 1, wherein R⁶ is selected from —C₁₋₆alkyl,—C₀₋₃alkylenearyl, and —C₀₋₃alkylene-C₃₋₇cycloalkyl.
 22. The compound ofclaim 1, wherein R⁷ is H.
 23. The compound of claim 1, wherein: r is 1;R¹ is selected from —COOR^(1a), —SO₂NHR^(1d), and tetrazol-5-yl; R^(1a)is H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl, —CH(C₁₋₄alkyl)OC(O)R^(1aa),—C₀₋₆alkylenemorpholine, or

R^(1aa) is —O—C₁₋₆alkyl or —O—C₃₋₇cycloalkyl; R^(1c) is —C₁₋₆alkyl,—C₀₋₆alkylene-O—R^(1ca), —C₁₋₅alkylene-NR^(1cb)R^(1cc), or—C₀₋₄alkylenearyl; R^(1ca) is H, —C₁₋₆alkyl, or—C₁₋₆alkylene-O—C₁₋₆alkyl; R^(1cb) and R^(1cc) are independentlyselected from H and —C₁₋₆alkyl, or are taken together as—(CH₂)₂—O—(CH₂)₂— or —(CH₂)₂—N[C(O)CH₃]—(CH₂)₂—; R^(1d) is —C(O)R^(1c)or —C(O)NHR^(1c); n is 0 or 1; R² is halo, —C₁₋₆alkyl, or—C₀₋₅alkylene-OR^(2b), and R^(2b) is H; R³ is —C₁₋₁₀alkyl or—C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b), and R^(3b) is —C₁₋₆alkyl; R^(5a) isH or —C(O)—R^(5aa); R^(5aa) is —C₁₋₆alkyl, —C₀₋₆alkylene-C₃₋₇cycloalkyl,-aminoC₄₋₇cycloalkyl, —C₀₋₆alkylenearyl, —C₀₋₆alkyleneheteroaryl,—C₀₋₆alkylenemorpholine, —C₀₋₆alkylenepiperazine-CH₃,—C₀₋₆alkylenepiperidine, —C₀₋₆alkylenepiperidine-CH₃,—CH[N(R^(5ab))₂]-aa where aa is an amino acid side chain,—C₀₋₆alkylene-CH[N(R^(5ab))₂]—R^(5ac), -2-pyrrolidine,-2-tetrahydrofuran, —C₀₋₆alkylene-OR^(5ab),—C₁₋₂alkylene-OC(O)—C₁₋₆alkyl, —Cl₁₋₄alkylene-COOH, or -arylene-COOH;R^(5ab) is independently H or —C₁₋₆alkyl; R^(5ac) is H, —C₁₋₆alkyl,—CH₂—C₃₋₇cycloalkyl, or —COOH; R^(5b) is —OH; R^(5c) is H; R^(5d) is Hor —Cl₁₋₄alkyl; R⁶ is selected from —C₁₋₆alkyl, —C₀₋₃alkylenearyl,—C₀₋₃alkyleneheteroaryl, and —C₀₋₃alkylene-C₃₋₇cycloalkyl; and R⁷ is H;each alkyl in R² is optionally substituted with 1 to 7 fluoro atoms; Arand each aryl and heteroaryl in R¹ and R⁵⁻⁶ is optionally substitutedwith 1 to 2 substituents independently selected from —C₁₋₆alkyl, halo,—O—C₁₋₆alkyl, and —NH₂, wherein each alkyl is optionally substitutedwith 1 to 5 fluoro atoms.
 24. The compound of claim 1, wherein X is—CH₂—NHC(O)— or —NHC(O)—.
 25. The compound of claim 24, wherein: r is 1;R¹ is selected from —COOR^(1a) and tetrazol-5-yl, where R^(1a) is H or—C₁₋₆alkyl; n is 1; R² is —C₁₋₆alkyl; R³ is —Cl₁₋₁₀alkyl; R⁵ is—C₀₋₃alkylene-SR^(5a), where R^(5a) is H or —C(O)—R^(5a), and R⁵ is—C₁₋₆alkyl; R⁶ is selected from —C₁₋₆alkyl, —C₀₋₃alkylenearyl, and—C₀₋₃alkylene-C₃₋₇cycloalkyl; and R⁷ is H.
 26. The compound of claim 1,wherein X is —C(O)NH—.
 27. The compound of claim 26, wherein: r is 1; R¹is selected from —COOR^(1a), —SO₂NHR^(1d), and tetrazol-5-yl; R^(1a) isH, —C₁₋₆alkyl, —C₁₋₃alkylenearyl, —CH(C₁₋₄alkyl)OC(O)R^(1aa),—C₀₋₆alkylenemorpholine, and

R^(1aa) is —O—C₁₋₆alkyl or —O—C₃₋₇cycloalkyl; R^(1c) is —C₁₋₆alkyl,—C₀₋₆alkylene-O—R^(1ca), —C₁₋₅alkylene-NR^(1cb)R^(1cc), or—C₀₋₄alkylenearyl; R^(1ca) is H, —C₁₋₆alkyl, or—C₁₋₆alkylene-O—C₁₋₆alkyl; R^(1cb) and R^(1cc) are independentlyselected from H and —C₁₋₆alkyl, or are taken together as—(CH₂)₂—O—(CH₂)₂— or —(CH₂)₂—N[C(O)CH₃]—(CH₂)₂—; R^(1d) is —C(O)R^(1c)or —C(O)NHR^(1C); n is 0 or 1; R² is halo, —C₁₋₆alkyl, or—C₀₋₅alkylene-OR^(2b), and R^(2b) is H; R³ is —C₁₋₁₀alkyl or—C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b), and R^(3b) is —C₁₋₆alkyl; R^(5a) isH or —C(O)—R^(5aa); R^(5aa) is —C₁₋₆alkyl, —C₀₋₆alkylene-C₃₋₇cycloalkyl,-aminoC₄₋₇cycloalkyl, —C₀₋₆alkylenearyl, —C₀₋₆alkyleneheteroaryl,—C₀₋₆alkylenemorpholine, —C₀₋₆alkylenepiperazine-CH₃,—C₀₋₆alkylenepiperidine, —C₀₋₆alkylenepiperidine-CH₃,—CH[N(R^(5ab))₂]-aa where aa is an amino acid side chain,—C₀₋₆alkylene-CH[N(R^(5ab))₂]—R^(5ac), -2-pyrrolidine,-2-tetrahydrofuran, —C₀₋₆alkylene-OR^(5ab),—C₁₋₂alkylene-OC(O)—C₁₋₆alkyl, —Cl₁₋₄alkylene-COOH, or -arylene-COOH;R^(5ab) is independently H or —C₁₋₆alkyl; R^(5a) is H, —C₁₋₆alkyl,—CH₂—C₃₋₇cycloalkyl or —COOH; R^(5b) is —OH; R^(5c) is H; R^(5d) is H or—Cl₁₋₄alkyl; R⁶ is selected from —C₁₋₆alkyl, —C₀₋₃alkylenearyl,—C₀₋₃alkyleneheteroaryl, and —C₀₋₃alkylene-1-C₃₋₇cycloalkyl; and R⁷ isH; each alkyl in R² is optionally substituted with 1 to 7 fluoro atoms;Ar and each aryl and heteroaryl in R¹ and R⁵⁻⁶ is optionally substitutedwith 1 to 2 substituents independently selected from —C₁₋₆alkyl, halo,—O—C₁₋₆alkyl, and —NH₂, wherein each alkyl is optionally substitutedwith 1 to 5 fluoro atoms.
 28. The compound of claim 27, wherein: r is 1;R¹ is —SO₂NHR^(1d); R^(1c) is —C₁₋₆alkyl, —C₀₋₆alkylene-O—R^(1ca),—C₁₋₅alkylene-NR^(1cb)R^(1cc), or —C₀₋₄alkylenearyl; R^(1ca) is H,—C₁₋₆alkyl, or —C₁₋₆alkylene-O—C₁₋₆alkyl; R^(1cb) and R^(1cc) areindependently selected from H and —C₁₋₆alkyl, or are taken together as—(CH₂)₂—O—(CH₂)₂— or —(CH₂)₂—N[C(O)CH₃]—(CH₂)₂—; R^(1d) is —C(O)R^(1c)or —C(O)NHR^(1C); n is 1; R² is —C₁₋₆alkyl; R³ is —C₁₋₁₀alkyl; R⁵ is—C₀₋₃alkylene-SR⁵ or —C₀₋₃alkylene-NR^(b)—C(O)R^(5d); R^(5a) is H or—C(O)—R^(5aa); R^(5aa) is —C₁₋₆alkyl; R^(5b) is —OH; R^(5d) is H; R⁶ is—C₁₋₆alkyl or —C₀₋₃alkylenearyl; and R⁷ is H.
 29. A pharmaceuticalcomposition comprising a compound of claim 1 and a pharmaceuticallyacceptable carrier.
 30. The pharmaceutical composition of claim 29,further comprising a second therapeutic agent selected from diuretics,β₁ adrenergic receptor blockers, calcium channel blockers,angiotensin-converting enzyme inhibitors, AT₁ receptor antagonists,neprilysin inhibitors, non-steroidal anti-inflammatory agents,prostaglandins, anti-lipid agents, anti-diabetic agents, anti-thromboticagents, renin inhibitors, endothelin receptor antagonists, endothelinconverting enzyme inhibitors, aldosterone antagonists,angiotensin-converting enzyme/neprilysin inhibitors, vasopressinreceptor antagonists, and combinations thereof.
 31. The compound ofclaim 1 prepared by the process comprising: (a) coupling a compound offormula 1 with a compound of formula 2:

to produce a compound having the formula:

where: A is —NH₂ and B is —COOH, or A is —COOH and B is —NH₂; the sum ofa and b is in the range of 0 to 11; Ar* is Ar—R¹*, where R¹* is R¹ or aprotected form of R¹; and R⁵* is R⁵ or a protected form of R⁵; thecarbon atoms in the —(CH₂)_(a) and —(CH₂)_(b) groups may be substitutedwith one or more R^(4b) groups; and one —CH₂— group in the —(CH₂)_(a) orthe —(CH₂)_(b) group may be replaced with —C₃₋₈cycloalkylene-,—CR^(4d)═CH—, or —CH═CR^(4d)—; and (b) when R¹* is a protected form ofR¹ and/or R⁵* is a protected form of R⁵, deprotecting the product ofstep (a) to produce a compound of formula I.
 32. A compound selectedfrom:

where r is 0, 1 or 2; Ar is:

Ar* is Ar—R¹*; R¹ is selected from —COOR^(1a), —NHSO₂R^(1b),—SO₂NHR^(1d), —SO₂H, —C(O)NH—SO₂R^(1c), —P(O)(OH)₂, —CN,—OCH(R^(1c))—COOH, tetrazol-5-yl,

where R^(1a) is H, —C₁₋₆alkyl, —C₁₋₃alkylenearyl,—C₁₋₃alkyleneheteroaryl, —C₃₋₇cycloalkyl, —CH(C₁₋₄alkyl)OC(O)R^(1aa),—C₀₋₆alkylenemorpholine,

R^(1aa) is —O—C₁₋₆alkyl, —O—C₃₋₇cycloalkyl, —NR^(1ab)R^(1ac), or—CH(NH₂)CH₂COOCH₃; R^(1ab) and R^(1ac) are independently selected fromH, —C₁₋₆alkyl, and benzyl, or are taken together as —(CH₂)₃₋₆—; R^(1b)is R^(1c) or —NHC(O)R^(1c); R^(1c) is —C₁₋₆alkyl,—C₀₋₆alkylene-O—R^(1ca), —C₁₋₅alkylene-NR^(1cb)R^(1cc),—C₀₋₄alkylenearyl or —C₀₋₄alkyleneheteroaryl; R^(1ca) is H, —C₁₋₆alkyl,or —C₁₋₆alkylene-O—C₁₋₆alkyl; R^(1cb) and R^(1cc) are independentlyselected from H and —C₁₋₆alkyl, or are taken together as—(CH₂)₂—O—(CH₂)₂— or —(CH₂)₂—N[C(O)CH₃]—(CH)₂—; R^(1d) is H, R^(1c),—C(O)R^(1c), or —C(O)NHR^(1c); R^(le) is —C₁₋₄alkyl or aryl; R¹* isselected from —C(O)O—P², —SO₂O—P⁵, —SO₂NH—P⁶, —P(O)(O—P⁷)₂,—OCH(R^(1e))—C(O)O—P², and tetrazol-5-yl-P⁴; n is 0, 1, 2 or 3; each R²is independently selected from halo, —NO₂, —C₁₋₆alkyl, —C₂₋₆alkenyl,—C₃₋₆cycloalkyl, —CN, —C(O)R^(2a), —C₀₋₅alkylene-OR^(2b),—C₀₋₅alkylene-NR^(2c)R^(2d), —C₀₋₃alkylenearyl, and—C₀₋₃alkyleneheteroaryl; where R^(2a) is H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl,—OR^(2b), or —NR^(2c)R^(2d); R^(2b) is H, —C₁₋₆alkyl, —C₃₋₆cycloalkyl,or —C₀₋₁alkylenearyl; and R^(2c) and R^(2d) are independently selectedfrom H, —Cl₁₋₄alkyl, and —C₀₋₁alkylenearyl; R³ is selected from—C₁₋₁₀alkyl, —C₂₋₁₀alkenyl, —C₃₋₁₀alkynyl, —C₀₋₃alkylene-C₃₋₇cycloalkyl,—C₂₋₃alkenylene-C₃₋₇cycloalkyl, —C₂₋₃alkynylene-C₃₋₇cycloalkyl,—C₀₋₅alkylene-NR^(3a)—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-O—C₀₋₅alkylene-R^(3b),—C₀₋₅alkylene-S—C₁₋₅alkylene-R^(3b), and —C₀₋₃alkylenearyl; where R^(3a)is H, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, or —C₀₋₃alkylenearyl; and R^(3b) isH, —C₁₋₆alkyl, —C₃₋₇cycloalkyl, —C₂₋₄alkenyl, —C₂₋₄alkynyl, or aryl; Xis —C₁₋₁₂alkylene-, where at least one —CH₂— moiety in the alkylene isreplaced with a —NR^(4a)—C(O)— or —C(O)—NR^(4a)—moiety, where R^(4a) isH, —OH, or —C₁₋₄alkyl; R⁵ is selected from —C₀₋₃alkylene-SR^(5a),—C₀₋₃alkylene-C(O)NR^(5b)R^(5c), and —C₀₋₃alkylene-NR^(5b)—C(O)R^(5d);where R^(5a) is H or —C(O)—R^(5aa); R^(5aa) is —C₁₋₆alkyl,—C₀₋₆alkylene-C₃₋₇cycloalkyl, -aminoC₄₋₇cycloalkyl, —C₀₋₆alkylenearyl,—C₀₋₆alkyleneheteroaryl, —C₀₋₆alkylenemorpholine,—C₀₋₆alkylenepiperazine-CH₃, —C₀₋₅alkylenepiperidine,—C₀₋₆alkylenepiperidine-CH₃, —CH[N(R^(5ab))₂]-aa where aa is an aminoacid side chain, —C₀₋₆alkylene-CH[N(R^(5ab))₂]—R^(5ac), -2-pyrrolidine,-2-tetrahydrofuran, —C₀₋₆alkylene-OR^(5ab), —O—C₀₋₆alkylenearyl,—C₁₋₂alkylene-OC(O)—C₁₋₆alkyl, —C₁₋₂alkylene-OC(O)—C₀₋₆alkylenearyl,—O—C₁₋₂alkylene-OC(O)O—C₁₋₆alkyl, —C₁₋₄alkylene-COOH, or -arylene-COOH;R^(5ab) is independently H or —C₁₋₆alkyl; R^(5ac) is H, —C₁₋₆alkyl,—CH₂—C₃₋₇cycloalkyl or —COOH; R^(5b) is H, —OH, —OC(O)R^(5ba), —CH₂COOH,—O-benzyl, -pyridyl, or —OC(S)NR^(5bb)R^(5bc); R^(5ba) is H, —C₁₋₆alkyl,aryl, —OCH₂-aryl, —CH₂O-aryl, or —NR^(5bb)R^(5bc); R^(5bb) and R^(5bc)are independently selected from H and —C₁₋₄alkyl; R⁵ is H, —C₁₋₆alkyl,or —C(O)R^(5ca); R^(5ca) is —C₁₋₆alkyl, —C₃₋₇cycloalkyl, aryl, orheteroaryl; R^(5d) is H, —C₁₋₄alkyl, —C₀₋₃alkylenearyl,—NR^(5da)R^(5db), —CH₂SH, or —O—C₁₋₆alkyl; R^(5da) and R^(5db) areindependently selected from H and —C₁₋₄alkyl; R⁵* is selected from—C₀₋₃alkylene-S—P³, —C₀₋₃alkylene-C(O)NH(O—P⁵), and—C_(O)-3alkylene-N(O—P⁵)—C(O)R^(5d); R⁶ is selected from —C₁₋₆alkvyl,—CH₂—O—(CH)₂OCH₃, —C₁₋₆alkylene-O—C₁₋₆alkyl, —C₀₋₃alkylenearyl,—C₀₋₃alkyleneheteroaryl, and —C₀₋₃alkylene-C₃₋₇cycloalkyl; and R⁷ is Hor is taken together with R⁶ to form —C₃₋₈cycloalkyl; wherein: each —CH—group in —(CH₂)— is optionally substituted with 1 or 2 substituentsindependently selected from —C₁₋₄alkyl and fluoro; each carbon atom inthe alkylene moiety in X is optionally substituted with one or moreR^(4b) groups and one —CH₂— moiety in X may be replaced with a groupselected from —C₃₋₈cycloalkylene-, —CR^(4d)═CH—, and —CH═CR^(4d)—; whereR^(4b) is —C₀₋₅alkylene-COOR^(4c), —C₁₋₆alkyl, —C₀₋₁alkylene-CONH₂,—C₁₋₂alkylene-OH, —C₀₋₃alkylene-C₃₋₇cycloalkyl, 1H-indol-3-yl, benzyl,or hydroxybenzyl; R^(4c) is H or —C₁₋₄alkyl; and R^(4d) is—CH₂—-thiophene or phenyl; each alkyl and each aryl in R¹⁻³, R^(4a-4d),and R⁵⁻⁶ is optionally substituted with 1 to 7 fluoro atoms; Ar and eacharyl and heteroaryl in R¹⁻³ and R⁵⁻⁶ is optionally substituted with 1 to3 substituents independently selected from —OH, —C₁₋₆alkyl,—C₂₋₄alkenyl, —C₂₋₄alkynyl, —CN, halo, —O—C₁₋₆alkyl, —S—C₁₋₆alkyl,—S(O)—C₁₋₆alkyl, —S(O)₂—C₁₋₄alkyl, -phenyl, —NO₂, —NH, —NH—C₁₋₆alkyl and—N(C₁₋₆alkyl)₂, wherein each alkyl, alkenyl and alkynyl is optionallysubstituted with 1 to 5 fluoro atoms; P² is a carboxy-protecting group;P³ is a thiol-protecting group; P⁴ is a tetrazole-protecting group; P⁵is a hydroxyl-protecting group; P⁶ is a sulfonamide-protecting group;and P⁷ is a phosphonate-protecting group or phosphinate-protectinggroup; and salts thereof.
 33. The compound of claim 32, selected fromthe group comprising: